No abstract

Diabetes prone biobreeding rats display several abnormalities in T cell numbers, T cell function and T cell surface phenotype which are associated with the onset of spontaneous disease. One of the most pronounced abnormalities in these animals is a marked T cell lymphopenia which is evident in both CD4+ and CD8+ peripheral T cell subsets. To gain a better understanding as to the nature of T cell responses in these animals, we have utilized RT-PCR to analyze the cytokine mRNA profiles of mitogen activated peripheral T cells derived from lymphopenic and non-lymphopenic animals. Our results suggest that inheritance of the lymphopenia gene, Lyp, is associated with a unique cytokine profile most similar to that previously described for mouse medullary thymocytes. In addition, cell surface staining of peripheral T cells from diabetes prone animals revealed a high frequency of Thyl+ cells, which is characteristic of both thymocytes and recent thymic emigrants. Following thymectomy, T cell responsiveness to a number of different stimuli is greatly reduced on a cell for cell basis as is the absolute number of surviving T cells. Taken collectively, our results suggest that the majority of the peripheral T cell pool in these diabetic prone rats consists of short lived, recent thymic emigrants which most likely also contain the effector cells required for initiation of diabetes.

Immunization of Lewis (LEW) rats with guinea pig myelin basic protein (MBP) induces a population of encephalitogenic CD4 T cells having specificity for the dominant immunogenic peptide of MBP, 68-86. The TCR g chains of these disease-causing T cells show three distinct features: they are almost exclusively V g 8.2, they use AspSer as the first two amino acid residues of the third complementarity-determining region (CDR3) and these junctional region sequences show few if any non-germline N-region nucleotide additions. This last feature raises the possibility that these autoimmune T cell precursors derive from TCR gene rearrangements occurring during early, perinatal ontogeny, a period when the enzyme terminal deoxynucleotidyl transferase (TdT), responsible for N region additions, is not expressed. An alternative possibility is that these features of the TCR of MBP 68-86-reactive T cells are dictated by considerations of antigen selection throughout ontogeny both in the thymus and in the periphery -i.e., that such g chains are conformationally the most appropriate for triggering by an epitope of 68-86 complexed to class II RT1.B l MHC molecules. We show here that active experimental allergic encephalomyelitis, while delayed in onset, occurs in heavily irradiated animals, but not in the absence of a thymus, a finding indicating that this autoimmune disease is caused by a T cell subpopulation derived from the post-irradiation adult thymus. These disease-causing T cells are heavily V g 8.2+ , CDR3 AspSer + and use few N region additions. We conclude that T cells with these TCR g chain features can be generated in the adult thymus and most likely reflect requirements imposed by antigen selection.

Immunization of Lewis (LEW) rats with guinea pig myelin basic protein (MBP) induces a population of encephalitogenic CD4 T cells having specificity for the dominant immunogenic peptide of MBP, 68-86. The TCR beta chains of these disease-causing T cells show three distinct features: they are almost exclusively Vbeta8.2, they use AspSer as the first two amino acid residues of the third complementarity-determining region (CDR3) and these junctional region sequences show few if any non-germline N-region nucleotide additions. This last feature raises the possibility that these autoimmune T cell precursors derive from TCR gene rearrangements occurring during early, perinatal ontogeny, a period when the enzyme terminal deoxynucleotidyl transferase (TdT), responsible for N region additions, is not expressed. An alternative possibility is that these features of the TCR of MBP 68-86-reactive T cells are dictated by considerations of antigen selection throughout ontogeny both in the thymus and in the periphery--ie., that such beta chains are conformationally the most appropriate for triggering by an epitope of 68-86 complexed to class II RT1.BI MHC molecules. We show here that active experimental allergic encephalomyelitis, while delayed in onset, occurs in heavily irradiated animals, but not in the absence of a thymus, a finding indicating that this autoimmune disease is caused by a T cell subpopulation derived from the post-irradiation adult thymus. These disease-causing T cells are heavily Vbeta8.2+, CDR3 AspSer+ and use few N region additions. We conclude that T cells with these TCR beta chain features can be generated in the adult thymus and most likely reflect requirements imposed by antigen selection.