The Role of TCR Specificity in the Regulation of the Immune Response to Self and Commensal Antigens

ABSTRACT OF THE DISSERTATION The Role of TCR Specificity in the Regulation of the Immune Response to Self and Commensal Antigens by Stephanie K. Lathrop Doctor of Philosophy in Biology and Biomedical Sciences: Immunology) Washington University in St. Louis, 2010 Dr. Chyi-Song Hsieh, Chairperson The immune system must be able to fight potentially pathogenic microbial invaders without mounting an attack on its own tissues, food antigens, and harmless or beneficial commensal species. Despite the elimination of many self-reactive T cells in the thymus, some T cells with the ability to recognize self and potentially cause autoimmune disease are present in the periphery. The population of CD4+ regulatory T cells: Treg) expressing the transcription factor Foxp3 are required to actively maintain homeostasis of the immune system, but it is uncertain whether their function is antigen-specific. These studies address the repertoire of the variable T cell receptor expressed on each T cell, in an attempt to understand the role of specificity in the maintenance of tolerance. By sequencing of the TCR&alpha chain on cells expressing a fixed TCR&beta chain, we are able to compare the repertoire of TCRs on T cells from different populations. These studies revealed that Treg use a repertoire of TCRs distinct from that of the CD4+CD44hi activated/memory or CD44lo naïve T cell subsets, and that it varies considerably depending upon the location of the cells. This data suggests that Treg home to and/or develop in areas in which they recognize antigen, presumably self antigens on the tissues which they protect. Most Treg develop their regulatory phenotype in the thymus; however, it is known that mature T cells can develop into Treg outside of the thymus, a process termed peripheral conversion. While we see evidence of a very small amount of contribution by peripheral conversion to the Treg repertoire of the spleen and lymph nodes, it has been proposed that the gut immune system is a major site of conversion. Therefore we studied the TCR repertoire of the colon, and indeed find that the colonic Treg TCRs are very unique, and many of them recognize commensal bacterial antigens. We further show that thymocytes expressing these TCRs do not upregulate Foxp3 expression in the thymus, and for two of these TCRs, we show that Foxp3 expression depends upon the composition of the intestinal microbiota. Therefore, our data supports a model in which Foxp3+ regulatory cells show antigen specificity for the tissues they protect, and in some cases develop in situ, allowing for tolerance to antigens that are not thymically presented