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A W Goldrath

Publications and source records attributed to A W Goldrath.

11 recordsLinked to original sources
PubMed2000

Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation.

In a depleted lymphoid compartment, naive T cells begin a slow proliferation that is independent of cognate antigen yet requires recognition of major histocompatibility complex-bound self-peptides. We have followed the phenotypic and functional changes that occur when naive CD8(+) T cells undergo this type of expansion in a lymphopenic environment. Naive T cells undergoing homeostasis-driven proliferation convert to a phenotypic and functional state similar to that of memory T cells, yet distinct from antigen-activated effector T cells. Naive T cells dividing in a lymphopenic host upregulate CD44, CD122 (interleukin 2 receptor beta) and Ly6C expression, acquire the ability to rapidly secrete interferon gamma, and become cytotoxic effectors when stimulated with cognate antigen. The conversion of naive T cells to cells masquerading as memory cells in response to a homeostatic signal does not represent an irreversible differentiation. Once the cellularity of the lymphoid compartment is restored and the T cells cease their division, they regain the functional and phenotypic characteristics of naive T cells. Thus, homeostasis-driven proliferation provides a thymus-independent mechanism for restoration of the naive compartment after a loss of T cells.

Adoptive Transfer↗
PubMed2000

Competition for specific intrathymic ligands limits positive selection in a TCR transgenic model of CD4+ T cell development.

Efficient positive selection of a broad repertoire of T cells is dependent on the presentation of a diverse array of endogenous peptides on MHC molecules in the thymus. It is unclear, however, whether the development of individual TCR specificities is influenced by the abundance of their selecting ligands. To examine this, we analyzed positive selection in a transgenic mouse carrying a TCR specific for the human CLIP:I-Ab class II complex. We found that these mice exhibit significantly reduced CD4+ T cell development compared with two other transgenic mice carrying TCRs selected on I-Ab. Moreover, many of the selected cells in these mice express endogenous and transgenic receptors as a consequence of dual TCRalpha expression. Dramatic enhancement of the selection efficiency is observed, however, when fewer transgenic cells populate the thymus in mixed bone marrow chimeras. These results suggest that positive selection is limited by the availability of selecting peptides in the thymus. This becomes apparent when large numbers of thymocytes compete for such peptides in TCR transgenic animals. Under such conditions, thymocytes appear to undergo further TCRalpha gene rearrangement to produce a receptor that may be selected more efficiently by other thymic self-peptides.

Animals↗
PubMed2000

T-cell memory: You must remember this ...

While antigen-inexperienced (naive) T cells appear to require constant tickling of their receptor by self-antigens for homeostasis, antigen-experienced (memory) T cells have no such requirement. An implication is that long-term T-cell memory does not depend on persisting antigen.

Animals↗
PubMed1999

Selecting and maintaining a diverse T-cell repertoire.

To provide a T-cell population that will respond promptly to foreign antigen, the immune system looks inward, using the variety of self-antigens to select and maintain a diverse repertoire of receptors. A protective immune system must include a T-lymphocyte population that is poised to respond to foreign antigenic peptides presented by self-major histocompatibility complex molecules. As the organism cannot predict the precise pathogen-derived antigens that will be encountered, the system uses the diverse array of self-peptides bound to self-major histocompatibility complex molecules, not only to select a receptor repertoire in the thymus, but also to keep naïve T cells alive and 'ready for action' in the periphery.

Animals↗
PubMed1999

Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts.

In the absence of thymic emigration, the peripheral T cell pool is maintained by division of mature lymphocytes. We have examined the molecular interactions required for peripheral CD8+ T cell expansion in lymphopenic mice without conventional antigenic stimulation. Expansion of CD8+ T cells in lymphopenic hosts was found to be peptide specific. An antagonist peptide known to serve as a ligand for positive selection of these T cells promoted expansion; however, a control peptide that binds the same class I molecule did not. Surprisingly, the cells undergoing proliferation in lymphopenic hosts did not mature to cytotoxic effectors and displayed a partially activated surface phenotype. These data suggest that division of T cells in the periphery of lymphopenic hosts requires specific recognition of self-peptide/MHC complexes, similar to the signal for thymocyte maturation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Triggers of autoimmune disease in a murine TCR-transgenic model for multiple sclerosis.

The combination of genetic and environmental factors that contribute to human autoimmune responses has made potential triggers of these diseases difficult to identify. We examined how experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis, is triggered using TCR-transgenic mice specific for myelin basic protein (MBP). In these TCR-transgenic mice, EAE can be actively induced and also occurs spontaneously. The incidence of spontaneous EAE in this model is largely confined to adolescence and early adulthood and is more prevalent among males than females, indicating that hormonal influences may contribute to triggering central nervous system autoimmune disease. Disease induction studies show that not all stimuli that activate MBP-specific T cells in vivo also induce EAE. Immunization with MBP peptide stimulates the transgenic T cells to produce Th1 cytokines; however, the activated T cells do not accumulate in the central nervous system and induce EAE unless pertussis toxin is also administered. EAE can be induced by intrathecal injection of either stimulated or nonstimulated transgenic T cells into nontransgenic or transgenic recipients. Therefore, gaining access to the central nervous system appears to be the critical step in this model for the induction of EAE, regardless of the activation state of the T cells.

Animals↗
PubMed1997

Virus-mediated delivery of antigenic epitopes into dendritic cells as a means to induce CTL.

Dendritic cells (DC) are potent inducers of CD8+ T cells and can stimulate protective antitumor immunity when pulsed with an antigenic peptide or protein. We used a replication-deficient adenovirus containing a Kb-restricted antigenic peptide of chicken OVA to study CTL induction in vitro and in vivo after adenovirus-mediated gene transfer into DC. The efficiency of adenovirus-infected DC in eliciting a specific CTL response was compared with immunizations with a recombinant vaccinia virus and DC pulsed with peptide or protein. An immortalized DC line derived from a C57BL/6 mouse and freshly isolated splenic DC from C57BL/6 mice were used in CTL induction. Virus-infected DC elicited the strongest Ag-specific CTL response in vitro and in vivo and induced protective antitumor immunity to a challenge with EG.7 tumors (EL-4 cell line expressing OVA). Direct immunization of mice with recombinant adenovirus resulted in the induction of high titers of neutralizing Abs, which precluded a boost of a CTL response after repeated inoculations. However, repeated injections of virus-infected DC induced only low titers of neutralizing Abs. Furthermore, the presence of neutralizing Abs specific for the virus did not affect the usefulness of infected DC as repeated applications of virus-infected DC boosted the CTL response even in mice previously infected with the recombinant vector. The use of DC infected with a recombinant virus has advantages over other forms of immunization and could provide an alternative approach for designing vaccination therapies.

Adenoviridae↗
PubMed1997

CD8 lineage commitment in the absence of CD8.

The absence of cytotoxic T lymphocyte activity and the failure of MHC class I-restricted T cell receptor (TCR) transgenic thymocytes to mature in CD8alpha-deficient mice suggest that CD8 may be essential for CD8 lineage commitment. We report that variants of the antigenic peptide that delete TCR transgenic thymocytes from CD8 wild-type but not CD8alpha-deficient mice can restore positive selection of CD8 lineage cells in the absence of CD8. The positively selected cells down-regulate CD4, up-regulate TCR, respond to the antigenic peptide, and express CD8beta mRNA. Interestingly, there was no enhanced selection of CD4+ T cells, implying that the TCR-MHC interaction, even in the absence of CD8, provided instructive signaling for commitment to the CD8 lineage. Our results are discussed in terms of recent models of T cell lineage commitment.

Animals↗
PubMed1995

T cell recognition of major histocompatibility complex class II complexes with invariant chain processing intermediates.

Peptides from the lumenal portion of invariant chain (Ii) spanning residues 80-106 (class II-associated Ii peptide [CLIP]) are found in association with several mouse and human major histocompatibility complex (MHC) class II allelic variants in wild-type and presentation-deficient mutant cells. The ready detection of these complexes suggests that such an intermediate is essential to the MHC class II processing pathway. In this study, we demonstrate that T cells recognize CLIP/MHC class II complexes on the surface of normal and mutant cells in a manner indistinguishable from that of nominal antigenic peptides. Surprisingly, T cell hybrids specific for human CLIP bound to murine MHC class II molecule I-Ab and a new monoclonal antibody 30-2 with the same specificity, recognize two independent epitopes expressed on this peptide/class II complex. T cell recognition is dependent on a Gln residue (position 100) in CLIP, whereas the 30-2 antibody recognizes a Lys residue-at position 90. These two residues flank the 91-99 sequence that is conserved among human, mouse, and rat Ii, potentially representing an MHC class II-binding site. Our results suggest that the COOH-terminal portion of CLIP that includes TCR contact residue Gln 100 binds in the groove of I-Ab molecule. Moreover, both T cells and the antibody recognize I-Ab complexed with larger Ii processing intermediates such as the approximately 12-kD small leupeptin-induced protein (SLIP) fragments. Thus, SLIP fragments contain a CLIP region bound to MHC class II molecule in a conformation identical to that of a free CLIP peptide. Finally, our data suggest that SLIP/MHC class II complexes are precursors of CLIP/MHC class II complexes.

Alleles↗
PubMed1995

Differences in adhesion markers, activation markers, and TcR in islet infiltrating vs. peripheral lymphocytes in the NOD mouse.

Insulin dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse is the result of a cellular mediated autoimmune event that destroys pancreatic islet beta cells. This destruction is characterized by a progressive lymphocytic infiltration into the islets as well as circulating autoantibodies and T cells reactive with islet antigens. To gain a better understanding of the cells responsible for islet destruction we isolated lymphocytes from the islets of prediabetic NOD mice and conducted a comparative phenotypic analysis with the analogous subpopulations of lymphocytes isolated from peripheral blood and lymph node (LN) of the same mice. CD3+ cells were analysed for T cell receptor (TcR); cell bearing gamma delta TcR were consistently observed at a higher frequency in the infiltrating T cells than in the periphery. Lymphocytes were also characterized for the expression of CD4 and CD8 T cell markers and, within each population, for the expression of activation markers (CD25, CD69) and adhesion markers (CD51, CD54, CD11b, CD49e, L-selectin). Significantly increased levels of CD4+CD8+ double-positive and CD4-CD8- double-negative T cell populations were observed in the infiltrating lymphocytes as compared with peripheral lymphocytes. In addition, within both CD4 and CD8 subpopulations isolated from islet infiltrates, CD11b+ and CD49e+ cells were increased with respect to the same subset of cells isolated from the periphery. In contrast, the level of cells that expressed L-selectin was significantly higher in the periphery for both CD4+ and CD8+ cells than for infiltrating cells. These data describe the phenotype of islet reactive T cells in the NOD mouse and identify possible targets for therapeutic intervention.

Animals↗