CD4+CD25+ T-Cells Control Autoimmunity in the Absence of B-Cells

Abstract

OBJECTIVETumor necrosis factor ligand family members B-cell–activating factor (BAFF) and a proliferation-inducing ligand (APRIL) can exert powerful effects on B-cell activation and development, type 1 T-helper cell (Th1) immune responses, and autoimmunity. We examined the effect of blocking BAFF and APRIL on the development of autoimmune diabetes.RESEARCH DESIGN AND METHODSFemale NOD mice were administered B-cell maturation antigen (BCMA)-Fc from 9 to 15 weeks of age. Diabetes incidence, islet pathology, and T- and B-cell populations were examined.RESULTSBCMA-Fc treatment reduced the severity of insulitis and prevented diabetes development in NOD mice. BCMA-Fc–treated mice showed reduced follicular, marginal-zone, and T2MZ B-cells. B-cell reduction was accompanied by decreased frequencies of pathogenic CD4+CD40+ T-cells and reduced Th1 cytokines IL-7, IL-15, and IL-17. Thus, T-cell activation was blunted with reduced B-cells. However, BCMA-Fc–treated mice still harbored detectable diabetogenic T-cells, suggesting that regulatory mechanisms contributed to diabetes prevention. Indeed, BCMA-Fc–treated mice accumulated increased CD4+CD25+ regulatory T-cells (Tregs) with age. CD4+CD25+ cells were essential for maintaining euglycemia because their depletion abrogated BCMA-Fc–mediated protection. BCMA-Fc did not directly affect Treg homeostasis given that CD4+CD25+Foxp3+ T-cells did not express TACI or BR3 receptors and that CD4+CD25+Foxp3+ T-cell frequencies were equivalent in wild-type, BAFF−/−, TACI−/−, BCMA−/−, and BR3−/− mice. Rather, B-cell depletion resulted in CD4+CD25+ T-cell–mediated protection from diabetes because anti-CD25 monoclonal antibody treatment precipitated diabetes in both diabetes-resistant NOD.μMT−/− and BCMA-Fc–treated mice.CONCLUSIONSBAFF/APRIL blockade prevents diabetes. BCMA-Fc reduces B-cells, subsequently blunting autoimmune activity and allowing endogenous regulatory mechanisms to preserve a prehyperglycemic state.

Rotavirus acceleration of murine type 1 diabetes is associated with a T helper 1-dependent specific serum antibody response and virus effects in regional lymph nodes

“…Additionally, the elevated expression of MHC suggests that the presentation of antigen to T cells is enhanced, so the possibility of T cell molecular mimicry remains [10,41]. CD4 + and CD8 + T cells are critical for diabetes development, while B cells contribute to T cell priming [42][43][44][45]. RRV infection increases the number of B cell in PLN and islets and the number of CD8 + T cells in islets [13], supporting the proposed role of RRV interactions with APC in lymphocyte activation.…”

Regulatory B cells in autoimmune diseases

“…53 Recent studies conducted by Grey and colleagues have shown that B-cell depletion delays and reduces diabetes by increasing the number of CD25 1 Foxp3 1 CD4 1 Treg T cells, thereby enforcing long-term tolerance. 54 Moreover, studies by Smith and Tedder have suggested that Breg cells, such as B10 cells, may represent a significant component of the reconstituted B-cell pool after B-cell depletion. 55 These findings suggest an involvement of Breg cells in the development of diabetes.…”

TACI-Ig induces immune balance of Th cells in MLN via BLyS/APRIL-receptors signaling in rats with adjuvant-induced arthritis

“…Taken together with in vitro study, T cells secreted more IFN-γ and less IL-4 or IL-5 in the stimulation of BLyS, which suggest that BLyS may be a Th1 response-promoting and Th2 response-suppressing cytokine. Further studies showed that B cell reduction by BLyS blockade is accompanied by decreased frequencies of pathogenic CD4 + CD40L + T cells and reduced IL-17 levels, suggesting that BLyS levels may correlate positively with production of IL-17 [41]. We demonstrated that TACI-Ig could regulate Th cell-mediated immune responses by modulating balance of Th1/Th2 and Treg/Th17 cell in MLN of AA rats.…”