The long-term goal of this project is an understanding of the costimulatory signals that antigen-presenting cells (APC) provide to naive T cells to regulate T cell antigen receptor (TCR)-driven clonal expansion and memory cell formation. CD28 and CTLA-4, which prefer CD86 and CD80 as ligands, are the most potent positive and negative costimulatory receptors for naive T cells, respectively. Blockade of CD28 is now approved for the treatment of rheumatoid arthritis, and inhibition of CTLA-4 is being tested in humans to enhance tumor immunity. Despite these promising advances, many questions remain as to how CD28 and CTLA-4 actually regulate immunity. For example, the consequences of TCR signaling in the absence of CD28 are still not clear with anergy, death, and ignorance all viable possibilities. In addition, our current lack of understanding concerning the specificity of the T cells that cause disease in the absence of CTLA-4 is a barrier to understanding how this molecule prevents autoimmunity. We suggest that many of these uncertainties are related to a past reliance on unphysiologic in vitro activation stimuli or monoclonal T cells with fixed affinity for one peptide:MHC (pMHC) ligand. In contrast, we will use a new method based on pMHCII tetramers and magnetic bead enrichment to study CD28 and CTLA-4 effects on polyclonal CD4+ T cells with a normal range of affinities for a pMHCII. In the first aim, we will test the idea that CD28 signals in two distinct modes, one relying on TCR co-clustering and a YMNM motif in the cytoplasmic tail and another involving a PYAP motif that is independent of TCR co-clustering. We hypothesize that the co-clustering mode is critical for pMHCII sensing by clones with low affinity TCRs.
These aims will be pursued by measuring clonal expansion, contraction, phenotype conversion, TCR affinity, and memory cell formation by polyclonal pMHCII-specific naive CD4+ T cells lacking one or both of the signaling modes during development and the primary immune response.
The second aim i s to determine if CTLA-4 constrains the activation of CD4+ T cells expressing TCRs with high affinities for self pMHCII. The hypothesis will be tested in CTLA-4-deficient mice with candidate self pMHCII and by using CD4+ T cell clones from the diseased organs of CTLA-4-deficient mice and an expression cloning system to identify their TCR ligands. This set of experiments has the potential to provide a clear picture of CD28 and CTLA-4 function under physiologically-relevant conditions for T cells with a range of TCR affinities. Narrative: These studies are relevant because they focus on molecules (CD28 and CTLA-4) that regulate the quality of the immune response by T lymphocytes. Several promising therapies based on blockade of these molecules are in use or development for the treatment of arthritis, transplant rejection, and cancer. The plan described in this application is designed to further the understanding of the mechanisms by which CD28 and CTLA-4 control the immune response with the hope of improving the efficacy of the aforementioned treatments and extending them to other T cell-mediated diseases.
|Taylor, Justin J; Pape, Kathryn A; Steach, Holly R et al. (2015) Humoral immunity. Apoptosis and antigen affinity limit effector cell differentiation of a single naïve B cell. Science 347:784-7|
|Linehan, Jonathan L; Dileepan, Thamotharampillai; Kashem, Sakeen W et al. (2015) Generation of Th17 cells in response to intranasal infection requires TGF-?1 from dendritic cells and IL-6 from CD301b+ dendritic cells. Proc Natl Acad Sci U S A 112:12782-7|
|Yang, Jessica A; Tubo, Noah J; Gearhart, Micah D et al. (2015) Cutting edge: Bcl6-interacting corepressor contributes to germinal center T follicular helper cell formation and B cell helper function. J Immunol 194:5604-8|
|Nelson, Ryan W; Beisang, Daniel; Tubo, Noah J et al. (2015) T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity. Immunity 42:95-107|
|Tubo, Noah J; Pagán, Antonio J; Taylor, Justin J et al. (2013) Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153:785-96|
|Nelson, Ryan W; McLachlan, James B; Kurtz, Jonathan R et al. (2013) CD4+ T cell persistence and function after infection are maintained by low-level peptide:MHC class II presentation. J Immunol 190:2828-34|
|Pagán, Antonio J; Peters, Nathan C; Debrabant, Alain et al. (2013) Tracking antigen-specific CD4+ T cells throughout the course of chronic Leishmania major infection in resistant mice. Eur J Immunol 43:427-38|
|Pagán, Antonio J; Pepper, Marion; Chu, H Hamlet et al. (2012) CD28 promotes CD4+ T cell clonal expansion during infection independently of its YMNM and PYAP motifs. J Immunol 189:2909-17|
|Taylor, Justin J; Martinez, Ryan J; Titcombe, Philip J et al. (2012) Deletion and anergy of polyclonal B cells specific for ubiquitous membrane-bound self-antigen. J Exp Med 209:2065-77|
|Taylor, Justin J; Pape, Kathryn A; Jenkins, Marc K (2012) A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med 209:597-606|
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