CD8+ T cells maintain tolerance to myelin basic protein by 'epitope theft'

Abstract

Myelin basic protein-specific CD8(+) T cells can induce central nervous system autoimmunity; however, immune tolerance prevents these autoreactive cells from causing disease. To define the mechanisms that mediate tolerance, we developed two T cell receptor-transgenic mouse lines with different affinities for the H-2K(k)-restricted myelin basic protein epitope consisting of amino acids 79-87 (MBP(79-87)). We observed both thymic deletion and peripheral tolerance in the lower-affinity T cells. The higher-affinity T cells, however, showed no evidence of tolerance induction and were able to prevent tolerance of the lower-affinity T cells by removing H-2K(k)-MBP(79-87) complexes from antigen-presenting cells without proliferating. This form of immune regulation could limit responses of self-reactive T cells that escape other tolerance mechanisms.

Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein

“…Thymocytes in MHC class I-restricted MBP79-87-specific 8.6 TCR transgenic mice on a WT (MBP ϩ/ϩ ) background are deleted at a late stage of maturation, manifested by a loss of mature CD8 single-positive (SP) HSA (CD24) lo CD3 ϩ thymocytes (11). To define the role of classic MBP in this central tolerance, we bred 8.6 mice onto the golli Ϫ/Ϫ background.…”

“…C3HeB/FeJ (C3H), C3Fe.SWV-Mbp shi /J (MBP Ϫ/Ϫ ), and C3.129P2(B6)-B2m tm1Unc /J (␤2m Ϫ/Ϫ ) mice were from The Jackson Laboratory. TCR-transgenic (8.6) mice have been described previously (11). Golli Ϫ/Ϫ mice were a kind gift from A. Campagnoni (University of California, Los Angeles) and were backcrossed 10 generations onto the C3H background, except for the 6-week-old 8.6 golli Ϫ/Ϫ mice in Fig.…”

“…We analyzed tolerance in this system by using MBP79-87-specific T cell receptor (TCR) transgenic (8.6) mice, MBP-deficient (MBP Ϫ/Ϫ ) mice that do not express any golli or classic MBP isoforms containing MBP79-87 (12), and golli-deficient (golli Ϫ/Ϫ ) mice that have unaltered classic MBP expression but do not express any golli isoforms (13). We found that classic MBP synthesized by nonBM-derived cells was sufficient to tolerize MBP79-87-specific T cells (11); however, the source of classic MBP, the cell types presenting this epitope, and the role of golli in tolerance induction were not investigated.…”

“…TECs did not induce tolerance in these T cells. CD8 ϩ MHC class I-restricted thymocytes specific for MBP79-87, an epitope in both classic and golli MBP, are also deleted in the thymus (11). We analyzed tolerance in this system by using MBP79-87-specific T cell receptor (TCR) transgenic (8.6) mice, MBP-deficient (MBP Ϫ/Ϫ ) mice that do not express any golli or classic MBP isoforms containing MBP79-87 (12), and golli-deficient (golli Ϫ/Ϫ ) mice that have unaltered classic MBP expression but do not express any golli isoforms (13).…”

T cell receptors in an IL-10-secreting amino acid copolymer-specific regulatory T cell line that mediates bystander immunosuppression

“…Two TCR-transgenic mouse lines (C3H background, H-2K ϩ ) expressing different MBP79-87-specific TCR (V␣8/V␤6 or V␣8/V␤8) were generated. T cells expressing V␣8/V␤6 TCR were subjected to both central and peripheral tolerance, while T cells expressing the other TCR showed no evidence of tolerance induction, implying that the TCR itself may confer epigenetic regulation (34).…”