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PubMed1984

Interaction of African trypanosomes with the immune system.

African trypanosomes cause disease in man and domestic animals. The parasites have the ability to escape immune control by two means: by antigenic variation of the surface glycoprotein coat so that waves of variant parasites arise and by inducing a general immunosuppression affecting immune responses to the parasite as well as to parasite-unrelated antigens. The cellular basis of the immune dysfunction will be discussed in relation to a mouse model system - it is the result of proliferative stimuli to T- or B-cells which then become refractory to selection by antigen and normal control signals. Recent experiments have focused on macrophages as important direct target cells for parasite action. We have obtained no evidence for a parasite derived mitogen acting directly on B- or T-cells. In vitro cell proliferation is associated with accessory cells and relates only to T-cells. During infection, macrophages become activated with changes in receptor expression and mediator release, so that there is, for example, spontaneous IL-1 release (with a role in T- and possibly in B-cell proliferation) and several-fold increases in PGE2 secretion, with its immunosuppressive activities. We also find parasitaemia-associated release of alpha-beta and gamma interferon by various cells which in turn influences immune function. The active parasite component is associated with parasite membranes, but its nature has not been further defined. We proposed that the macrophage changes provide a general pathway causing immune dysfunction associated with many infections, be they parasitic or caused by other invading organisms.

Adjuvants, Immunologic↗

PubMed1992

Monoclonal antibodies anti-CD3, anti-TCR alpha beta and anti-CD2 act synergistically with tumor cells to stimulate lymphokine-activated killer cells and tumor-infiltrating lymphocytes to secrete interferon gamma.

Peripheral blood lymphocytes cultured in interleukin-2 IL-2 acquire the ability to recognize and kill a wide range of tumor cells. Such promiscuous killer cells are termed lymphokine-activated killer (LAK) cells. We recently reported that the interaction of LAK cells with tumor cells stimulated the LAK cells to release interferon (IFN) gamma. Here, we report that the release of IFN gamma by LAK cells can be further enhanced by addition of the monoclonal antibodies (mAbs), anti-CD3, anti-(T cell receptor alpha beta) (TCR alpha beta) and a mitogenic combination of anti-CD2 (T112 + T113). Other antibodies, including a non-mitogenic anti-CD2 mAb (Leu5b), that recognize T cell-associated antigens were not stimulatory. The same stimulatory mAbs also synergized with tumor cells to stimulate tumor-infiltrating lymphocytes (TIL) to secrete IFN gamma. Additional experiments indicated that it was the T cell subset of LAK cells (LAK-T cells) that was stimulated by tumor cells and mAbs to release IFN gamma. Inhibition studies with specific mAbs suggest that the stimulation of IFN gamma release by LAK-T cells was dependent both on the aggregation of TCR-CD3 complexes on the LAK-T cell, and on the interaction of accessory molecules with their ligands. The accessory molecules we have identified as critical are LFA 1 and CD2/LFA-2 on LAK-T cells interacting with their respective ligands ICAM-1 and LFA3. Thus our data suggest that cytokine production in LAK-T cells can be regulated by multiple molecular interactions, involving the TCR-CD3 complex and adhesion molecules.

Antibodies, Monoclonal↗

PubMed1991

Cytokine regulation of the mucosal immune system: in vivo stimulation by interferon-gamma of secretory component and immunoglobulin A in uterine secretions and proliferation of lymphocytes from spleen.

The secretory immune system in the female reproductive tract is known to be regulated by sex hormones and antigen. The purpose of the present study was to examine the control by interferon-gamma (IFN gamma) of the secretory component (SC), the polymeric immunoglobulin A (IgA) receptor, and IgA in uterine secretions and to determine whether IFN gamma influences the proliferation of spleen cells in response to mitogens. When measured by RIA, SC levels in uterine secretions were elevated when increasing doses of IFN gamma (1000-5000 U/uterus) were placed in the uterine lumen of ovariectomized rats. In contrast, IFN alpha-beta (5000 U/uterus) placed in the uterine lumen had no effect on uterine SC levels. To determine whether IgA movement increases in response to IFN gamma, animals were treated with estradiol to increase uterine tissue IgA levels without stimulating the accumulation of IgA or SC in uterine secretions. Under these conditions, intrauterine IFN gamma increased SC and IgA levels in uterine secretions, suggesting that in vivo IFN gamma stimulation of uterine SC increases the transport of IgA from tissue to lumen. Analysis of uterine tissues indicated that intrauterine IFN gamma had no apparent effect on epithelial cell morphology. In contrast, intraepithelial lymphocytes and polymorphonuclear leucocytes, which were sparse in control tissues, increased markedly with IFN gamma treatment. This increase was antagonized when estradiol was administered along with IFN gamma. In other studies, IFN gamma placed in the uterine lumen significantly increased spleen cell proliferation in response to Concanavalin-A, phytohaemagglutinin, and lipopolysaccharide mitogens relative to those in spleen cells from control animals. These studies demonstrate that in vivo treatment with IFN gamma stimulates the mucosal immune system in the female reproductive tract by increasing SC and IgA levels in the uterine lumen and promoting the infiltration of intraepithelial lymphocytes and polymorphonuclear leucocytes into uterine tissue. Further, it suggests that antigen, in stimulating a local uterine response, may act through cytokines, particularly IFN gamma, to regulate the transport of IgA into uterine secretions as well as modulate lymphocyte proliferation at sites distal to the uterus.

Animals↗

PubMed1992

A cortisone sensitive CD3low subset of CD4+CD8- thymocytes represents an intermediate stage in intrathymic repertoire selection.

Two populations of CD4 single positive (SP) thymocytes were found in transgenic mice bearing class I-restricted Mls-1a reactive (V beta 8.1) TCR genes in the absence of the restriction element. CD3high CD4 SP cells were deleted in the presence of Mls-1a and were cortisone resistant, whereas CD3low CD4 SP cells were not deleted in the presence of Mls-1a and were cortisone sensitive. Intravenous transfer of CD3low CD4 SP cells into nude mice resulted in significant peripheral expansion of these cells with apparent upregulation of CD3. These data indicate that CD3low CD4 SP thymocytes represent an intermediate stage in the transition from CD3low double positive (DP) to CD3high SP thymocytes and raise the possibility that these cells may hve undergone positive but not negative selection events (at least to Mls-1a). Furthermore the fact that CD3high DP thymocytes were also deleted by Mls-1a in these mice suggests strongly that sensitivity to Mls-1a deletion is dependent upon stage of thymic maturation (as revealed by TCR density) rather than CD4/CD8 phenotype.

Animals↗

PubMed1992

Evidence for early onset, polyclonal activation of T cell subsets in mice homozygous for lpr.

Mice homozygous for lpr and gld develop profound lymphadenopathy characterized by the accumulation of two functionally anergic T cell subsets, a predominant B220+CD4-CD8- double negative (DN) population and a minor, closely related CD4 dull+ B220+ population. Lymph nodes from diseased lpr and gld mice also contain abnormally high numbers of conventional T cells, and we reported recently that a high proportion of lpr and gld CD4+B220- T cells have the hallmarks of primed or memory T cells. In the present study, we further investigated the extent, ontogeny, and possible causes of T cell activation in lpr and gld mice. The criteria used to identify primed or memory T cells included activation-dependent increases in the expression of CD44, LFA-1, and the early activation Ag, CD69, and decreases in the expression of Mel-14 and CD45RB, as well as quantitative differences in the in vitro production of IFN-gamma and the TNF-alpha by stimulated cells. A comparison of TCR V beta gene utilization by lpr T cell subsets also was undertaken. The results showed that T cell activation was widespread and complex. CD8+ T cells exhibited a similar pattern of activation to CD4+B220- T cells. The activation of these two subsets occurred in parallel, was in evidence by 4 to 6 wk of age, and was both chronic and progressive. The proportions of CD44hiLFA-1hi, CD4+B220-, and CD8+ T cells increased steadily between 4 and 20 wk of age, but changes in T cell growth, Mel-14, and CD45RB expression and cytokine secretion were not observed until mice were older than 11 wk. A very different pattern of activation was observed for B220+ T cells. At all ages, B220+ DN and CD4+B220+ T cells were CD44hiMel-14hi and 60 to 75% were CD69+. The expression of CD69 appeared to be stimulus dependent rather than constitutive, suggesting that these cells, too, may be chronically stimulated in vivo. In keeping with their anergic state, DN T cells responded poorly to cross-linking of CD69. The stimuli inducing chronic activation of CD4+B220- and CD8+ T cells are unlikely to include inappropriate reactions to autoantigens because there was no evidence for selective accumulation of CD4+ or CD8+ T cells bearing particular V beta genes or potentially self-reactive cells that normally are deleted in the thymus. By comparison, C3H-lpr DN cells displayed some potentially significant differences in V beta 6 and V beta 9 expression from CD4+B220- and CD8+ T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Locally superantigen-activated peritoneal cytolytic T lymphocytes belong to the CD8+ CD45RC- subset and lyse MHC class II+ tumor cells.

Bacterial encoded superantigens (SA) are capable of activating and targeting cytolytic human and mouse T lymphocytes (CTL) to lyse major histocompatibility complex class II positive (MHC class II+) target cells. In this study both in vitro and in vivo activated rat CTL were directed against MHC II+ tumor targets by bacterial encoded SA. Polyclonal in vitro activation of rat peripheral blood T lymphocytes generated CTL capable of killing MHC class II+ human BSM cells coated by staphylococcal enterotoxin (SE) -A, -E, -D, and TSST-1 but not by SEB or SEC1-3. Allo selective peritoneal CTL generated by intraperitoneal stimulation with allogeneic spleen cells were directed against BSM cells by SEA, -D, and -E but not by SEB, SEC1-3 or TSST-1. Based on the above observations, and in order to locally activate CTL, SEA was chosen for in vivo priming of rats by intraperitoneal inoculation of the toxin. SEA injection generated highly cytolytic CTL, and maximum cytolytic responses were seen at 50-250 micrograms SEA per animal with a peak in response 48-72 hours after injection of the toxin. The cytolytic activity of peritoneal SEA reactive effector cells was confined to the TCR alpha beta+ CD4- CD8+ CD45RC- cell population. MHC class II- colon carcinoma cells were insensitive to lysis by SEA reactive CTL but colon carcinoma cells induced to express MHC class II by interferon-gamma (IFN-gamma) treatment were efficiently lysed in the presence of SEA. Comparison of rat and human MHC II+ colon carcinomas revealed a peak in sensitivity to lysis at 10-100 ng SEA/ml for both tumor targets. These findings suggest that superantigens can be used in local immunotherapy of peritoneal tumors such as ovarian and colorectal carcinomatosis, with inducible or constitutive expression of MHC class II.

Animals↗

PubMed1992

Distinct antigen presenting cell-derived signals induce TH cell proliferation and expression of effector cytokines.

In addition to the stimulus delivered by the specific interaction of the T cell receptor (TCR) and the antigen - MHC class II complex, activation of resting helper T lymphocytes (TH) requires several poorly defined accessory cell-derived co-stimulatory signals. Here we provide evidence that proliferation and expression of effector cytokine genes by TH cells are induced by distinct co-stimulatory signals. Normal murine splenic TH cells were activated by Staphylococcus aureus enterotoxin B (SEB) superantigen and various antigen presenting cells (APCs) to proliferate, differentiate into TH cells blasts, and secrete cytokines. Blast transformation and proliferation of TH cells is achieved with macrophages and other splenic APCs, like B cells. Expression of the cytokines interferon gamma (IFN gamma), IL-5, and IL-2 by TH cells, however, is to various degrees dependent on the presentation of SEB by macrophages. The requirement for macrophages is particularly striking for the expression of IFN gamma. Thus macrophages provide distinct co-stimulatory signals for cytokine secretion and proliferation. The results suggest that B cells induce clonal expansion of TH cells whereas macrophages additionally promote terminal differentiation of activated TH cells into TH effector cells.

Animals↗

PubMed1993

Evolution of a CD3+CD4+ alpha/beta T-cell receptor+ mature T-cell clone from CD3-CD7+ sorted human bone marrow cells.

In order to study extrathymic differentiation in vitro, CD7+CD3- lymphocytes were sorted from normal human bone marrow and cultured under conditions of limiting dilution together with irradiated pooled allogeneic peripheral blood mononuclear cells (PBMC) and phytohemagglutinin (PHA) in the presence of 1000 U/ml of interleukin-2 (IL-2). One clone was obtained that failed to react with monoclonal antibody (mAb) TCR delta 1 (TCR1, gamma/delta-specific) or WT31 (TCR2, alpha/beta-specific). From day 35 through day 74 in culture, the surface phenotype of this clone evolved into CD3+, CD4+, CD8-, TCR2+, TCR1-, and was further characterized as CD2+, CD45RO+, CD16-, and CD56-. The presence of mRNA for TCR alpha and beta but not gamma and delta chains was confirmed by Northern blotting. Accessory cell-dependent autocrine proliferative responses to PHA (most likely driven by IL-2) were initially absent, but became measurable at the same time as the TCR was acquired. However, in the absence of PHA, the clone failed to respond to a panel of homozygous B-cell lines representing the majority of MHC class II alleles. Autoreactivity was also not demonstrable. Cytotoxicity was limited to MHC unrestricted "natural killer (NK)-like" lysis of K562 target cells, with no autocytotoxicity detected. The NK-like lysis diminished over time in parallel with the acquisition of surface TCR. The cloned cells were not suppressive for mature lymphocyte proliferation. After stimulation, the cells secreted tumor necrosis factor alpha and granulocyte/macrophage colony-stimulating factor (GM-CSF) detected by immunoassays, and T-cell growth factors, most likely IL-2, as detected by bioassays. Polymerase chain-reaction methods demonstrated the presence of mRNA for IL-2, IL-3, IL-4, IL-9, interferon-gamma, and GM-CSF in these cells after stimulation with PHA and B-LCL. These results suggest that cells with the phenotype and some functional characteristics of mature T lymphocytes can evolve extrathymically in vitro from T-cell precursors sorted from normal human bone marrow.

Antigens, CD↗

PubMed1994

CD57+ T lymphocytes are derived from CD57- precursors by differentiation occurring in late immune responses.

CD3+ T cells expressing the 110-kDa CD57 antigen are found in survivors of renal, cardiac and bone marrow transplants, in patients with acquired immune deficiency syndrome and in patients with rheumatoid arthritis. They are also present in normal individuals and expand upon ageing. They do not grow in culture and their role in the immune response is poorly understood. The expression of the various isoforms of the leukocyte common antigen (CD45) identifies a spectrum of differentiation in CD4+ and CD8+ T cells ranging from naive (CD45RA+CD45RBbrightCD45RO-) through early primed cells (CD45RA-RBbrightROdull) to highly differentiated memory cells which are CD45RA-RBdullRObright. CD45 isoforms expressed by CD57+ T cells showed distinct differences between CD4+ and CD8+ populations, but in each case indicated an advanced state of differentiation. The expression of T cell receptor V beta families was highly variable between individuals, but both CD57+ and CD57- cells show a full range of the specificities tested. V beta expression was more closely related within either the CD4+ or the CD8+ subsets, irrespective of CD57 expression, than between these subsets, suggesting a relationship between CD57+ and CD57- cells within the same T cell pool. This possibility was supported by experiments showing that CD3+CD57+ lymphocytes were similar to CD3+CD57- T cells in terms of the production of basic T cell cytokines [interleukin (IL)-2, IL-4, and interferon-gamma]. Furthermore, in vitro stimulation of CD3+CD57- T cells in secondary mixed leukocyte reaction or by co-culture with IL-2 and IL-4 induced the appearance of CD3+CD57+ cells with phenotypic and functional similarities to in vivo CD3+CD57+ cells. These data strongly suggest that the expression of CD57 is a differentiation event which occurs on CD57- T cells late in the immune response.

Antigens, CD↗

PubMed1993

Transformation of human T-cell clones by Herpesvirus saimiri: intact antigen recognition by autonomously growing myelin basic protein-specific T cells.

Herpesvirus saimiri has recently been shown to immortalize human T cells. It was unknown, however, whether Herpesvirus saimiri transformation affects T-cell receptor (TCR) expression and signal transduction. In the present study, we have transformed CD4+ human T-cell clones specific for human myelin basic protein. The transformed T cells were grown in interleukin 2 and divided in the absence of antigen and antigen-presenting cells. They retained the membrane phenotype of activated T cells and secreted the cytokines interferon gamma and lymphotoxin, but interleukin 4 was not detected. Further, the transformed T cells continued to express the original TCR as demonstrated by TCR variable-region-V beta-specific monoclonal antibodies and TCR sequencing. Antigen-specific recognition and signal transduction by the TCR were demonstrated by myelin-basic-protein-induced HLA-DR-restricted secretion of interferon gamma and lymphotoxin and by myelin-basic-protein-specific proliferation. Antigen specificity and reactivity have been maintained for > 1 year after transformation. Transformation with Herpesvirus saimiri now allows the production of virtually unlimited numbers of (auto)antigen-specific T cells expressing functional TCR and a stable membrane phenotype. This technology will facilitate studies of the pathogenesis of putative autoimmune diseases, such as multiple sclerosis, and may be of help in TCR-targeted immunotherapy.

Antigens, CD↗

PubMed1991

Igh-1b-specific CD4+CD8- T cell clones of the Th1 subset selectively suppress the Igh-1b allotype in vivo.

The demonstration of major histocompatibility complex (MHC)-restricted T helper (Th) cells specific for peptides from the variable (V) regions of syngeneic immunoglobulin (Ig) (idiopeptides) opens the possibility that Th cells regulate B cell functions via idiopeptide-based cognate T-B interactions. As a model for such interactions we investigated the influence of Ig allotype-specific T cells on the differentiation of H-2-syngeneic B cells expressing that particular Ig allotype. We established a BALB/c (H-2d, Iga) CD4+CD8- T cell line and clones of the Th1 subset (interleukin 2+, interleukin 4-, interferon-gamma+, tumor necrosis factor-alpha+) that recognized Igh-1 (IgG2a) of the b allotype (Igh-1b) together with I-Ad. These T cells specifically suppressed surface Igh-1b+ B cells in vitro and in vivo. In 12 out of 15 6-week-old (BALB/c X B10.D2)F1 mice neonatally injected with Igh-1b-specific T cells, the serum Igh-1b concentrations were less than 5% of the levels in the controls. Thus, allotype suppression can be accomplished solely by adoptive transfer of Igh-1b-specific CD4+ T cells. The in vivo suppression was specific for Igh-1b+ B cells as the recipients' levels of Igh-1a and Igh-4b (IgG1b) were unaffected. The V beta 14-specific anti-T cell receptor (TcR) monoclonal antibody 14-2 inhibited activation of hybridomas derived from two of the clones. Collectively the data indicate that suppression resulted from cognate interactions between allopeptide-specific TcR alpha/beta+ T cells and normal unmanipulated B lymphocytes presenting their endogenous Igh-1b in association with MHC class II molecules. The data support the possibility that normal B cells can be suppressed by idiopeptide-specific T cells in vivo.

Animals↗

PubMed1992

CD4+ suppressor cells of autoimmune encephalomyelitis respond to T cell receptor-associated determinants on effector cells by interleukin-4 secretion.

We have previously demonstrated that CD4+ suppressor T cells (Ts) inhibit the secretion of interferon (IFN)-gamma, but not interleukin (IL)-2, by effector cells of experimental autoimmune encephalomyelitis (EAE). Moreover, CD4+ Ts appear to regulate IFN-gamma by secretion of transforming growth factor-beta. We now show that CD4+ Ts produce a lymphokine with IL-4 activity in response to a determinant associated with EAE effector cells. CD4+ Ts do not proliferate or secrete IFN-gamma, IL-2, or IL-4 in response to myelin basic protein, nor do CD4+ Ts proliferate or secrete IL-2 when co-cultured with irradiated EAE effector cells. Rather, CD4+ Ts secrete IL-4 when co-cultured with either irradiated effector spleen cells or irradiated encephalitogenic line cells. CD4+ Ts do not secrete IL-4 in response to OVA-primed spleen cells, suggesting that the suppressor cells recognize a determinant specific to encephalitogenic T cells. Furthermore, CD4+ Ts secrete IL-4 when cultured with synthetic T cell receptor (TcR) V beta 8, but not TcR V beta 14 peptide, in the presence of antigen-presenting cells. This response is major histocompatibility complex class II restricted as demonstrated by inhibition of the response with anti-class II monoclonal antibody. These results suggest that CD4+ Ts recognize a determinant associated with TcR on the surface of EAE effector cells and respond by secreting IL-4, in a manner analogous to the Th2 lymphocyte subtype.

Amino Acid Sequence↗

PubMed1994

Fine antigen specificity of human gamma delta T cell lines (V gamma 9+) established by repetitive stimulation with a serotype (KTH-1) of a gram-positive bacterium, Streptococcus sanguis.

We have established human gamma delta T cell lines specific for Streptococcus sanguis (S. sanguis) KTH-1 present in normal oral cavity flora. The CD4-CD8-CD3+V gamma 9+V delta 1-CD45RO+ CD25+ T cell lines showed a proliferative response to the streptococcal antigen (Ag) in the presence of autologous antigen-presenting cells without apparent evidence of HLA restriction. The proliferative response of the gamma delta T cell lines was completely blocked by anti-TcR gamma delta monoclonal antibody (mAb) and anti-HLA class I mAb (W6/32), whereas anti-HLA classical class Ia mAb (B-H9; anti-HLA-A,B,C), anti-HLA class II mAb (anti-DR, anti-DQ, and anti-DP) and anti-CD4 mAb did not have any inhibitory effects. Surprisingly, the gamma delta T cell lines showed the proliferative response against the original bacterial Ag KTH-1 exclusively, and exhibited no cross-reactivity with nominal Ag such as purified protein derivative of tuberculin, tetanus toxoid and Mycobacterium tuberculosis, or the same species but different strain of S. sanguis, American Type Culture Collection (ATCC) standard strain (10556), or even with the same strain but different serotype of S. sanguis, KTH-3. Moreover, cytokine production of the gamma delta T cell lines was similar to the Th1 pattern [interferon-gamma, tumor necrosis factor (TNF)-alpha and TNF-beta]. They also produced interleukin-8 that functions as one of chemoattractants for polymorphonuclear cells. Using direct sequencing technique of the polymerase chain reaction products, we found that junctional diversity of the T cell receptor (TcR) used by the parental KTH-1 specific gamma delta T cell line and its subclones is rather limited. It is suggested that gamma delta T cells with canonical TcR could preferentially respond to KTH-1 Ag. Thus, in addition to a broad or cross-reactivity of gamma delta T cells against phylogenetically conserved stress/heat-shock protein, which is well characterized by others, some peripheral blood gamma delta T cells could recognize and kill exogenous agents with fine antigenic specificity to protect the body against them.

Antigens, Bacterial↗

PubMed1991

Proliferation of double-negative (CD4-CD8-) T cells bearing T-cell receptor-alpha beta in a haemophiliac with human immunodeficiency virus type 1 infection and factor VIII inhibitor: functional properties of double-negative T-cell receptor-alpha beta+ T cells.

We present a patient with haemophilia A showing human immunodeficiency virus type 1 (HIV-1) infection and factor VIII inhibitor in whom a novel T-cell subpopulation, double-negative (CD4-CD8-) T cells bearing T-cell receptor (TCR)-alpha beta, proliferated polyclonally in the peripheral blood. An interleukin-2-dependent T-cell line with a CD4-CD8-TCR-alpha beta+ phenotype was established from the peripheral blood lymphocytes of the patient, and its biological functions were studied. It was found that the CD4-CD8-TCR-alpha beta+ T cells possessed both HLA-unrestricted cytotoxicity and helper function for immunoglobulin production by B cells. In addition, these T cells were found to produce interferon-gamma and interleukin-2 following activation via CD3-TCR complexes. These data demonstrating the multifunction of these newly defined CD4-CD8-TCR-alpha beta+ T cells thus suggest that these cells play an important role in protection against HIV infection. The mechanism of production of factor VIII inhibitor in the present case is also discussed focusing on the CD4-CD8-TCR-alpha beta+ T cells.

Adult↗

PubMed1992

Limited T-cell receptor beta-chain diversity of a T-helper cell type 1-like response to Mycobacterium leprae.

Delayed-type hypersensitivity (DTH) is the standard measure of T-cell responsiveness to infectious organisms. For leprosy, the Mitsuda reaction, a local immune response to cutaneous challenge with Mycobacterium leprae, is considered to represent a measure of DTH against the pathogen. We analyzed the diversity of the T-cell receptor beta-chain repertoire in Mitsuda reactions to determine the breadth of the mycobacterial antigens involved. The polymerase chain reaction was used to compare V beta usage in the Mitsuda reaction T-cell lines established and unstimulated peripheral blood. These molecular analyses revealed a skewed T-cell receptor V beta gene usage in the Mitsuda reaction and in T-cell lines from lesions. To examine the reactivity of T cells from these lesions, T-cell lines were tested against the available native and recombinant antigens of M. leprae. T-cell lines derived from Mitsuda reactions responded more strongly to the 10-kDa M. leprae antigen, a homolog of GroES in Escherichia coli, than to other M. leprae proteins. T-cell lines were also shown to proliferate strongly in response to the 17- and 3-kDa proteins. The pattern of the lymphokine mRNA of these cells was reminiscent of the pattern of murine TH1 cells, positive for interleukin-2 and gamma interferon and weakly positive for interleukin-4. These data indicate that a limited array of T cells, perhaps recognizing stress proteins, secrete a type 1 lymphokine profile in the DTH response to mycobacteria.

Antigens, Bacterial↗

PubMed1992

Roles of alpha beta and gamma delta T cell subsets in viral immunity.

The current status of T-cell subset involvement in viral immunity is summarized for experimental studies in mice. The immunobiology of the normal host response is discussed, with particular reference to lymphocytic choriomeningitis (LCM) and influenza. The general impression is that CD8+ cytotoxic T lymphocytes, CD4+ TH1 cells, gamma interferon, and IL-2 are of major importance, with these different components of the immune system interacting to promote an optimal response. However, experiments with a variety of virus systems indicate that there is considerable plasticity, at least in young, adult mice. Other mechanisms often compensate if a key lymphocyte subset is absent throughout the development of the immune response. Influenza-infected mice depleted of either CD4+ or CD8+ T cells clear virus and recover, though the latter may not be true for the elimination of LCM virus. Emerging information on the involvement of gamma delta T cells in viral pneumonia is summarized, but there is as yet no understanding of the biological significance (if any) of these lymphocytes in viral immunity. The point is made that alpha beta T-cell memory to viruses is long-lived, and the need for antigen persistence to maintain such memory is questioned.

Animals↗

PubMed1991

Genotypic and phenotypic evidence of T-cell leukemia in a patient successfully treated by interferon-alpha for typical hairy cell leukemia.

A 53-year-old man was diagnosed to have typical hairy cell leukemia. Immunophenotyping of frozen splenic tissue showed clonality of hairy cells for mu lambda, confirmed by the corresponding immunoglobulin gene rearrangements. The patient was successfully treated with interferon-alpha (IF-alpha). In the fifth year of treatment with IF-alpha the morphology of peripheral blood mononuclear cells (PBMC) and of bone marrow infiltration changed with the appearance of numerous small to intermediate shaped lymphocytes of a T-helper phenotype. Frank leukemia, resistant to IF-alpha treatment and ultimately aggressive chemotherapy, developed. Emergence of this second clonal disease was confirmed by rearrangement studies performed on PBMC; rearrangements of both alleles of the TCR beta were identified, whereas the JH and lambda IVS genes were in germline configuration. The outgrowth of a second, malignant T-cell clone paralleled by the disappearance (down-regulation?) of the initial B-cell clone while under cytokine treatment is consistent with the possibility that IF-alpha favoured the emergence of this second clone.

Bone Marrow↗

PubMed1987

Establishment and characterization of an undifferentiated human T leukemia cell line which requires granulocyte-macrophage colony stimulatory factor for growth.

A human leukemia cell line (TALL-101) was established from the bone marrow of a patient with an undifferentiated acute T cell leukemia using the conditioned medium (CM) of the human T cell leukemia virus (HTLV) II-transformed human cell line J-LB1. Immunofluorescence analysis on the original leukemic cells indicated the presence of T cell markers (Leu-1, Tdt, and T11); however, the established TALL-101 cell line expressed only antigens commonly present on progenitor cells, thymocytes, and myelomonocytic cells, but not on mature T cells. A high percentage of TALL-101 cells displayed the Tac antigen which was down-regulated upon incubation in the presence of recombinant human (rH) interleukin 2 (IL 2). Interferon (IFN)-gamma induced the appearance of class II histocompatibility leukocyte antigens (HLA) and of a T cell marker (3A1), and enhanced the expression of transferrin receptors on these cells. Further evidence for a T cell lineage of the TALL-101 cell line was provided by both chromosomic and genotypic analysis showing a translocation in chromosome 14 typical of T cell leukemias, and a rearrangement of the T-beta receptor locus. The growth-promoting activity in the J-LB1-CM was identified as granulocyte-macrophage colony stimulatory factor (GM-CSF), a growth factor which stimulates proliferation of normal myelomonocytic cells and other progenitor cells, but not known to have an effect on T cells. Dose response curves of [3H]thymidine incorporation and growth indicated that TALL-101 cells were sensitive to very low concentrations of rHGM-CSF, 5 ng/ml inducing maximal proliferation in chemically defined medium. The TALL-101 cell line is strictly GM-CSF-dependent for growth: upon depletion of GM-CSF from the culture medium, the cells stop proliferating immediately and die within 1 to 2 wk. The overall data, showing that GM-CSF is able to support the growth of a highly undifferentiated T cell leukemia, strongly suggests that this factor might have similar growth promoting effects on other immature T cell leukemias, and possibly, on normal T cell progenitors.

Antigens, Differentiation, T-Lymphocyte↗