Functional Tolerance of CD8+ T Cells Induced by Muscle-Specific Antigen Expression

Abstract

Skeletal muscles account for more than 30% of the human body, yet mechanisms of immunological tolerance to this tissue remain mainly unexplored. To investigate the mechanisms of tolerance to muscle-specific proteins, we generated transgenic mice expressing the neo-autoantigen OVA exclusively in skeletal muscle (SM-OVA mice). SM-OVA mice were bred with OT-I or OT-II mice that possess a transgenic TCR specific for OVA peptides presented by MHC class I or class II, respectively. Tolerance to OVA did not involve clonal deletion, anergy or an increased regulatory T cell compartment. Rather, CD4+ T cell tolerance resulted from a mechanism of ignorance revealed by their response following OVA immunization. In marked contrast, CD8+ T cells exhibited a loss of OVA-specific cytotoxic activity associated with up-regulation of the immunoregulatory programmed death-1 molecule. Adoptive transfer experiments further showed that OVA expression in skeletal muscle was required to maintain this functional tolerance. These results establish a novel asymmetric model of immunological tolerance to muscle autoantigens involving Ag ignorance for CD4+ T cells, whereas muscle autoantigens recognized by CD8+ T cells results in blockade of their cytotoxic function. These observations may be helpful for understanding the breakage of tolerance in autoimmune muscle diseases.

Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury

“…CFSE-labeled OVA-specific Th cells (OT-II cells) neither proliferated nor expressed the activation marker CD69 after transfer into NOH mice ( Figure 1E). This was consistent with previous studies showing failure of OT-II cells to proliferate in response to OVA expressed as transgenic self antigen and has been explained by their limited affinity in particular for autoantigen (35,40,46). In summary, glomerular autoantigen was constitutively presented by DCs in the renal LNs, but only OT-I cells proliferated in response.…”

“…Mechanistic analysis revealed that Th cells acted by stimulating cross-presenting DCs in secondary lymphatics to permit cytotoxic effector function, whereas CTLs activated by unlicensed DCs ("help-less" CTLs) were programmed to die after secondary antigen encounters (43,44). Analogous mechanisms were reported in models used to examine different antigens or expression sites (45)(46)(47). Furthermore, Th cells may regulate the CTL effector phase in nonlymphatic organs (34,35,46).…”

“…Transgenic models such as that studied here generally use high numbers of autoreactive T cells (40,(45)(46)(47), which does not resemble clinical situations and therefore warrants caution in extrapolating results to human disease. Nevertheless, the requirement of very high numbers of autoreactive Th cells and CTLs, which needed to be stimulated by distinct DCs in different locations to induce immunopathology, indicated that several checkpoints exist to avoid T cell-mediated kidney disease.…”

“…Analogous mechanisms were reported in models used to examine different antigens or expression sites (45)(46)(47). Furthermore, Th cells may regulate the CTL effector phase in nonlymphatic organs (34,35,46). However, the rapid destruction of pancreatic islets by CTLs precluded elucidation of the underlying mechanisms in models in which antigen was expressed in this site.…”

Pathogenic aspects of dermatomyositis, polymyositis and overlap myositis

“…Using transgenic SM-OVA mice (selectively expressing OVA in skeletal muscle), bred with OVAspecific TCR Tg mice (OT-I or OT-II, restricted by MHC class I or class II, respectively) Olivier Boyer and his group elegantly showed that tolerance to muscle Ag (OVA neoAg) may not involve clonal deletion, anergy or an increased regulatory T-cell compartment as in other organs. Instead, they identified a tolerance mechanism in which CD4+ T-cells are tolerant by ignorance, whereas CD8+ T-cells become refractory to induction of a cytotoxic response [48]. Nevertheless, FOXP3 + regulatory T-cells (Treg), which main subset is also CD4+ CD25+, were recently to play a role in IIMs.…”