Negligible Role for Deletion Mediated by cDC1 in CD8+ T Cell Tolerance

Abstract

Deletion of CD8⁺ T cells by dendritic cells (DCs) is recognized as a critical mechanism of immune tolerance to self-antigens. Although DC-mediated peripheral deletion of autoreactive CD8⁺ T cells has been demonstrated using T cells reactive to model Ags, its role in shaping the naturally occurring polyclonal CD8⁺ T cell repertoire has not been defined. Using Batf3^-/- mice lacking cross-presenting CD8α⁺ and CD103⁺ DCs (also known as type 1 conventional [cDC1]), we demonstrate that peripheral deletion of CD8⁺ T cells reactive to a model tissue Ag is dependent on cDC1. However, endogenous CD8⁺ T cells from the periphery of Batf3^-/- mice do not exhibit heightened self-reactivity, and deep TCR sequencing of CD8⁺ T cells from Batf3^-/- and Batf3^+/+ mice reveals that cDC1 have a minimal impact on shaping the peripheral CD8⁺ T cell repertoire. Thus, although evident in reductionist systems, deletion of polyclonal self-specific CD8⁺ T cells by cDC1 plays a negligible role in enforcing tolerance to natural self-ligands.