TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets.
Foxp3-expressing regulatory T (T reg) cells derive primarily from selection in the thymus. Yet conversion of mature conventional CD4(+) T (T conv) cell lymphocytes can be achieved in several conditions, such as transforming growth factor beta treatment, homeostatic expansion, or chronic exposure to low-dose antigen. Such conversion might provide a means to generate peripheral tolerance by "converting" potentially damaging T cells that react to self-antigens. We tested this hypothesis in mice transgenic for the BDC2.5 T cell receptor (TCR), which is representative of a diabetogenic specificity that is naturally present in NOD mice and reactive against a pancreatic self-antigen. In the thymus, before any exposure to antigen, clonotype-positive T reg and T conv cells express a second TCRalpha chain derived from endogenous loci. High-throughput single-cell sequencing of secondary TCRs of the Valpha2 family showed their joining CDR3alpha regions to be very different in T reg and T conv cell thymocytes. These specific CDR3alpha motifs, thus, provided a "tag" with which to test the actual impact of T conv to T reg cell conversion in response to peripheral self-antigen; should the autoreactive clonotypic TCR induce T conv to T reg cell conversion upon encounter of cognate antigen in the pancreas or draining lymph node, one would expect to detect tag CDR3alpha motifs from T conv cells in the T reg cell populations. Sequencing large numbers of peripheral BDC(+)Valpha2(+) cells showed that little to no conversion occurs in response to this pancreatic autoantigen.
Wong
Jamie
J
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Mathis
Diane
D
Benoist
Christophe
C
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D019070:Cell Lineage; D004194:Disease; D005786:Gene Expression Regulation; D015321:Gene Rearrangement; D007111:Immunity, Cellular; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*
D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta