Peripheral CD4^loCD40⁺ auto‐aggressive T cell expansion during insulin‐dependent diabetes mellitus

Abstract

The generation of auto-aggressive T cells involves failure of central or peripheral tolerance. We previously demonstrated that peripheral CD4 lo CD40 + T cells give rise to pathogenic T cells in the non-obese diabetic (NOD) model. Here we show that peripheral CD4 + CD40 + T cells from diabetic or pre-diabetic NOD mice induce insulin-dependent diabetes mellitus. Consistent with breach of peripheral tolerance, CD4 lo CD40 + T cells expand with age in NOD mice but not in MHC-matched non-obese resistant (NOR) or BALB/c controls. Suggestive of a causal role for CD40 in autoimmunity, blocking CD40-CD154 interactions early during NOD development prevents autoaggressive T cell expansion while promoting increases in CD4 + CD25 + regulatory T cells. Importantly, CD40 signals promote expansion of V § 3.2 + and V § 8.3 + T cells. Furthermore, peripheral V § 3.2 + CD40 + T cells induce diabetes in NOD.scid recipients while V § 8.3 + T cells or V § 3.2 + -depleted T cell populations do not. This is the first demonstration that primary T cells transfer disease with the kinetics of auto-aggressive T cell clones and that specific TCR V § expansion promotes diabetes.

A Costimulatory Function for T Cell CD40

“…1 and Table I). Although the increase in CD40 ϩ cells in CIA vs control mice is modest compared with genetically predisposed autoimmune-prone strains of mice (14,17), it is consistent with the FACS profile of T cells from normal mice (9,17,67). Strains of mice that are prone to spontaneous autoimmune disease have robust expression of CD40 by T cells, whereas nondisease prone strains do not (14), so it is not surprising that C57BL/6 mice do not have as robust proportions of CD40 ϩ T cells as strains that develop autoimmune diseases relatively early in life.…”

“…The presence of CD40-expressing T cells or autoantibodies is not enough to develop autoimmunity. NOR mice, like their NOD counterparts, have CD40-expressing T cells, yet do not develop disease (17). Similarly, the presence of autoantibodies does not necessarily indicate pathogenesis (77)(78)(79).…”

“…Although a specific biologic role for CD40 on CD8 ϩ T cells remains undefined (10 -13), it has been shown that autoimmuneprone strains of mice have increased numbers of CD40 ϩ CD4 ϩ T cells compared with normal strains (14). The most extensively studied of these is the NOD mouse (15)(16)(17).…”

The Role of T Cells in Type 1 Diabetes

“…In numerous studies CD40 has been identified as a biomarker for auto-aggressive T cells (19,28,(32)(33)(34)(35)(36). A panel of highly pathogenic, auto-aggressive T cell clones, including the well described BDC2.5 clone express CD40 (34)(35)(36).…”

“…A panel of highly pathogenic, auto-aggressive T cell clones, including the well described BDC2.5 clone express CD40 (34)(35)(36). Although CD40 has been typically associated with antigen presenting cells, it was demonstrated on primary T cells in NOD mice, the type 1 diabetes model, and in the process identified a unique effector CD4 + T cell population, characterized as CD4 + CD40 + [Th40] (19,28,(32)(33)(34)(35)(36)(37). Importantly, Th40 cells were detected in both autoimmune and non-autoimmune mouse strains but occurring at a significantly greater percentage and cell number in autoimmunity (19,28,(32)(33)(34)(35).…”