Lymphocyte survival: a red queen hypothesis.
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Animals↗
Biomedical subjects
A A Freitas
Publications and source records attributed to A A Freitas.
Differential requirements for survival and proliferation of CD8 naïve or memory T cells.
The requisite molecular interactions for CD8 T cell memory were determined by comparison of monoclonal naïve and memory CD8(+) T cells bearing the T cell receptor (TCR) for the HY antigen. Naïve T cells required only the right major histocompatibility complex (MHC) class I-restricting molecule to survive; to expand, they also needed antigen. In contrast, for survival, memory cells did not require the restricting MHC allele, but needed only a nonspecific class I; for expansion the correct class I, but not antigen, was required. Thus, maintenance of CD8 T cell memory still required TCR-MHC class I interactions, but memory T cells may have a lower functional activation threshold that facilitates secondary responses.
Adoptive Transfer↗
Resource competition as a mechanism for B cell homeostasis.
Cellular competition for survival signals offers a cogent and appealing mechanism for the maintenance of cellular homeostasis [Raff, M. C. (1992) Nature (London) 356, 397-400]. We present a theoretical and experimental investigation of the role of competition for resources in the regulation of peripheral B cell numbers. We use formal ecological competition theory, mathematical models of interspecific competition, and competitive repopulation experiments to show that B cells must compete to persist in the periphery and that antigen forms a part of the resources over which B cells compete.
Animals↗
Independent homeostatic regulation of B cell compartments.
In the present study we used mice with a developmental arrest of B cell production to study the ability of a limited number of normal B cell precursors to populate peripheral B cell pools. In chimeras reconstituted with mixtures of bone marrow (BM) cells from normal and B cell-deficient donors, we show that the rate of BM B cell production is a constant function of the number of BM pre-B cells and is not modified by the peripheral B cell pool size, i.e. there is no feedback regulation of the central pre-B cell compartment by the number of mature B cells. We also show that the physiological number of peripheral B cells requires a minimum continuous input of newly formed cells, but is not determined by the number of B cell precursors. Chimeras with a threefold reduced rate of BM B cell production have normal numbers of peripheral B cells. Parabiosis between normal and B cell-deficient mice showed that the BM B cell production of one mouse suffices to replenish the B cell pool of three mice. Finally, we show that the compartment of activated IgM-secreting B cells is homeostatically autonomous since the number of cells it comprises is regulated independently of the size of the mature B cell pool. The results presented here support a model of the immune system in which the size of the different B cell compartments, i.e. pre-B, resting B and IgM-secreting, is autonomously regulated.
Animals↗
Lymphocyte homeostasis.
B- and T-lymphocyte populations have an independent homeostatic regulation of resting (B and T) and activated (B) or memory (T) cell compartments. This organization may provide an efficient mechanism to ensure simultaneously a first natural barrier of protection against common pathogens, the maintenance of immunological T-cell memory and a reservoir of repertoire diversity capable of dealing with new antigenic challenges.
Animals↗
Cellular competition modulates survival and selection of CD8+ T cells.
In this investigation we compare the repopulation of the CD8+ T cell compartments of bone marrow (BM) chimeras by either normal nontransgenic or T cell receptor (TcR) alpha beta-transgenic (TG) CD8+ T cells, the fate of TG and non-TG CD8+ T cells in different parabionts and the survival of TG and non-TG peripheral CD8+ T cells after transfer into athymic hosts. We found that cellular competition among CD8 T cells occurs at several steps of T cell differentiation including a) during the DN to DP transition, b) positive selection in the thymus, c) export from the thymus and d) in the periphery. Comparison of the results obtained in the BM chimeras and in the parabionts shows that an important step of T cell selection occurs during seeding of peripheral lymphoid tissues. Once established, peripheral T cells resist replacement by recent thymus migrants, i.e. in the periphery, selection of T cell repertoires follows the rule "first come, first served". Peripheral dominance correlates with T cell activation and division. Cell cycling and CD44 expression are more frequent among non-TG CD8 T cells than TG CD8 T cells and within the latter, more frequent among P14 TG CD8 T cells than anti-HYTG CD8 T cells. Thus, in the absence of intentional immunization, the frequencies of CD8+ T cells follow a hierarchy of selection in which non-TG > or = P14 TG > anti-HY TG. We also show that the equilibrium size and the fate of one CD8 T cell population differs according to the presence or absence of other CD8 T cell populations. Under these circumstances, selection of T cell repertoires and T cell survival and memory rely not only on the interactions of each T cell with their respective ligands, but also on the nature and number of other competing cells.
Animals↗
Persistence of V beta 6+ T cells in Mls-1a mice. A role for the third complementarity-determining region (CDR3) of the T cell receptor beta chain in superantigen recognition.
We have studied V alpha 2 and J beta usage by V beta 6+CD4+ peripheral T cells isolated from the congenic mice strains BALB/c (Mls-1b) and BALB.D2 (Mls-1a). We found that the TCR beta-chain of V beta 6+CD4+ T cells present in adult Mls-1a mice differed from those in Mls-1b mice; the fraction of V beta 6+CD4+T cells using the J beta 2.7 segment was reduced, while the number of V beta 6+CD4+ T cells using J beta 1.2 was augmented. These results indicate that the CDR3 region of the TCR beta-chain participates in recognition of the Mls superantigen. We also found that in Mls-1a mice an increased fraction of V beta 6+CD4+ T cells expressed the V alpha 2 chain. The study of J beta usage by V beta 6+CD4+V alpha 2+ and V beta 6+CD4+V alpha 2- T cells indicates that both J beta segment and TCR V alpha 2 chain expression confer complementary protection against deletion by Mls-1a superantigen. These results suggest a novel view of Mls-1a-driven selection, where the CDR3 region of the V beta chain modulates superantigen recognition, and the affinity/avidity of the TCR-MHC-superantigen complex determine the fate of the T cell.
Animals↗
Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance.
We studied the interactions of male-specific T cell receptor (TCR)-alpha/beta-transgenic (TG) cells with different concentrations of male antigen in vivo. We constructed mouse chimeras expressing different amounts of male antigen by injecting thymectomized, lethally irradiated mice with various ratios of male (immunoglobulin [Ig] Ha) and female (IgHb) bone marrow. These chimeras were injected with male-specific TCR-alpha/beta-trangenic cells. These experiments allowed us to monitor antigen persistence and characterize antigen-specific T cells in terms of their frequency, reactivity, and effector functions (as tested by elimination of male B cells in vivo). In the absence of antigen, virgin TG cells persisted but did not expand. Transient exposure to antigen resulted in cell expansion, followed by the persistence of increased numbers of antigen-reactive T cells. In contrast, antigen persistence was followed by two independent mechanisms of tolerance induction: anergy (at high antigen concentrations), where T cells did not differentiate into effector functions but persisted in vivo as unresponsive T cells, and exhaustion (at lower antigen concentrations), where differentiation into effector functions (B cell elimination) occurred but was followed by the disappearance of antigen-specific T cells.
Animals↗
The role of cellular competition in B cell survival and selection of B cell repertoires.
We studied the competitive repopulation by different B cells of irradiated mice reconstituted with bone marrow from either congenic or Ig-transgenic (TG) mice mixed at different ratios. We found that after reconstitution, the number of B cells recovered in the different chimeras is similar and independent of the ratio of injected cells. In chimeras hosting TG and non-TG cells, the relative representation of the donor cell lineages diverges from the ratios present in the inoculum, i.e. at the periphery, non-TG cells are preferentially selected. Selection of non-TG cells only occurs when population growth plateaus, i.e. when resources become limiting and competition starts to operate. Selection of non-TG cells depends on surface Ig expression, and they are selected because they have a longer survival. Finally, the life-expectancy of the same B cell population differs depending upon the second population present. The present results show that the life-span and the population size of each B cell clone can be altered (interfered with) by the presence of a second cell population, demonstrating the existence of cellular competition among B cells. Our findings establish the role of cellular competition in the selection of B cell repertoires and the existence of a hierarchy of B cell selection in the absence of antigenic stimulation. The implications of cellular competition on our understanding of the immune system are discussed.
Animals↗
External fixation of intertrochanteric fractures of the femur.
Forty patients with intertrochanteric fractures of the femur were treated by external fixation between July 1992 and April 1994. They were selected because of their high surgical risk, and evaluated by radiographs immediately after operation, and at 30 and 90 days. The results indicate that external fixation is a useful method of treatment for this type of patient.
Adolescent↗
Regulation of VH-gene expression is a lineage-specific developmental marker.
We have previously shown that in IgH congenic mice VH-gene family usage in neonatal spleen B cells and adult Ig-secreting cells is entirely determined by the IgH locus, while in adult resting B cells it is regulated by genetic element(s) located outside the IgH locus. Two observations reported here demonstrate that the differential expression of VH genes is an intrinsic property of the respective cell populations, determined by both the IgH locus and by a cis element(s) operating independently in the same animal. First, the study of F1 hybrids between the IgH congenic B6a and CB.20 strains demonstrates that cis elements control VH-gene family expression. Second, studies in irradiation chimeras showed that the environment in which cell differentiation proceeds is unable to overcome those controls. In chimeras of IgH congenic donors, VH-gene expression in fetal liver-derived splenic B cells and Ig-secreting cells is dictated by the IgH haplotype, while in bone marrow-derived B cells is entirely determined by the cis element(s). These results show a developmental and cell lineage-related restriction in VH-gene expression, and suggest that most adult splenic Ig-secreting cells may originate from precursors originally present in fetal liver, but which are rare among adult bone marrow precursors and CD5+ B cells.
Aging↗
Entry of B lymphocytes into the persistent cell pool in non-immunized mice is not accompanied by somatic mutation of VH genes.
In this study we compare VH-gene repertoires of short-lived and persistent B lymphocytes in normal nonimmunized mice. Enriched populations of persistent peripheral B cells were obtained in vivo either by (i) repeated injections with hydroxyurea or (ii) maintained ganciclovir administration to herpes simplex virus-1 thymidine kinase transgenic mice. Both approaches have previously been shown to deplete newly formed, short-lived B cells. VH genes expressed by persistent or unselected B cell populations were amplified by polymerase chain reaction, cloned using the lambda-ImmunoZAP system (Stratagene) and sequenced. The results presented here concern a total of 116 complete VH sequences from two VH gene families of established germ-line composition: VH7183 and VHX24. No differences were found between the two cell populations as to usage of D or JH segments and to the presence of N sequence additions at D/JH or VH/DJH junctions and CDR3 length. Over 90% of the sequenced VH genes were of germ-line arrangement with no evidence of somatic mutation. These results show that persistent B cells in normal mice are not of embryonic origin and that somatic hypermutation is not necessary for B cell survival. They also suggest that a significant fraction of persistent IgM+ B cells in normal mice are not generated by conventional antigenic stimulation and could represent a novel class of "memory" cells expressing germ-line repertoires.
Animals↗
VH-gene family dominance in ageing mice.
The cellular composition and VH-gene family repertoire were compared in different B-cell compartments from young adult (8-12 weeks) and old (18-24 months) C57BL/6 and BALB/c mice. Ageing mice were found to have a higher frequency of peripheral mature B cells utilizing genes from a single VH-gene family. While in each individual old C57BL/6 mice cells expressing the VH J558 gene family consistently were over-represented, a marked individual variation was observed in old BALB/c mice with increased frequency of either the VH J558, Q52 or J606 families. Aged mice were found also to have a reduced number of bone-marrow pre-B cells and an augmented number of splenic Ig-secreting cells. These results suggest that old mice express less diversified antibody repertoires possibly as a consequence of reduced input from precursors and increased peripheral selection, which may be responsible for the progressive establishment of immunodeficiency.
Aging↗
Lymphocyte lifespans: homeostasis, selection and competition.
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Animals↗
V region dependent selection of persistent resting peripheral B cells in normal mice.
In this study, we compare the VH gene family repertoire of persistent long-lived splenic B cells with that of the whole splenic B cell compartment. Persistent long-lived B cells were obtained by two independent strategies. Firstly, we studied cells that persist in the peripheral pools with or without cell division. We have transferred mature lipopolysaccharide (LPS)-reactive splenic B cells into LPS non-responder recipients and studied the donor population that could be recovered in host mice at differing time intervals after cell transfer. Secondly, we studied non-cycling resting long-lived B cells. These cells were obtained in normal mice after cytostatic treatment with hydroxyurea and in mice transgenic for the HSV-1 thymidine kinase gene after treatment with the anti-herpetic ganciclovir. Studying the VH gene family usage at the single level by in situ hybridization, we found that persistent B cells show an increased expression of the VHJ558 family and a diminished representation of the VH7183 family. These results demonstrate that in a normal non-immunized mouse, B cell survival and persistence in the resting state results from V region dependent selection.
Animals↗
Differential expression of VH gene families in peripheral B cell repertoires of newborn or adult immunoglobulin H chain congenic mice.
The pattern of VH gene family expression in the primary B cell repertoire of the mouse is strain dependent. In C57Bl/6 mice, the VH J558 family is expressed by more than 45% of the cells, while the expression of VH 7183, VH Q52, and VH 36-60 families together does not exceed 20%. In BALB/c mice, relative expression of VH J558 is lower than 35%, while the sum of the other three families reaches 25%. To assess which genetic loci control strain-specific VH gene family expression, we studied VH gene family usage in splenic B cell repertoires of different congenic strains of mice. Changes in major histocompatibility complex or immunoglobulin (Ig) K light chain genes did not modify VH gene family expression in adult mice. Differences at the IgH locus, however, modified VH gene family usage. In 1-d-old mice, the strain-specific VH gene family expression pattern is determined by the IgH haplotype. In adult mice, the VH gene family expression pattern of resting B cells is independent of the IgH locus and follows the genetic background of the congenic strain, while it is determined by the IgH haplotype among Ig-secreting spleen cells. In F1(B6 x BALB/c) mice, each of the two spleen B cell populations, sorted on the basis of mu heavy chain allotype expression, shows an independent VH gene family expression pattern, determined by the IgH locus. The implications of these results in the control of VH gene family expression, and in the selection of peripheral B cell repertoires are discussed.
Aging↗
Expression and selection of murine antibody repertoires.
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Animals↗
Normal serum immunoglobulins participate in the selection of peripheral B-cell repertoires.
In B-cell development, expression of immunoglobulin heavy-chain variable-region (VH) gene repertoires is determined by genetic mechanisms that favor rearrangement of the most D-proximal genes, resulting in overutilization of the VH7183 gene family early in ontogeny and in differentiating B cells of the adult bone marrow. Maturation of the immune system is accompanied by a decreased expression of VH7183 genes in the peripheral immunocompetent B-cell pool of adult animals. By comparing VH gene family expression in the bone marrow (emergent) and peripheral (available and actual) B-cell repertoires of germ-free and conventionally raised BALB/c mice, we found that peripheral selection of VH gene family utilization does not occur in germ-free animals. Reconstitution of germ-free mice with normal serum immunoglobulins purified from syngeneic donors reestablishes selection of VH7183-expressing B cells. Our results indicate that preimmune B-cell repertoires are selected in normal animals by environmental antigens and serum immunoglobulins.
Animals↗