Although it is established that defective clearance and, hence, increased accumulation of apoptotic cells can lead to autoimmunity, the mechanism by which this occurs remains elusive. Here, we observed that apoptotic cells undergoing secondary necrosis but not intact apoptotic cells provoked substantial immune responses, which were mediated through the toll-like receptor 2 (TLR2) pathway. The development of autoimmune diabetes was markedly inhibited in Tlr2(-/-) mice but not in Tlr4(-/-) mice, showing that TLR2 plays an important role in the initiation of the disease. Apoptotic beta-cell injury could stimulate the priming of diabetogenic T cells through a TLR2-dependent, but TLR4-independent, activation of antigen-presenting cells. These findings suggest that beta-cell death and its sensing via TLR2 may be an initial event for the stimulation of antigen-presenting cells and development of autoimmune diabetes.
Rheumatoid arthritis is a joint-specific autoimmune inflammatory disease of unknown etiology. The K/BxN mouse is a model of rheumatoid arthritis that is thought to be mainly due to autoantibody-mediated inflammatory responses. We showed previously that homeostatic proliferation of autoreactive CD4+ T cells is required for disease initiation in the K/BxN mice. In this study, we show that the homeostatically proliferating CD4+CD25− T cells produce IL-21. We generated IL-21R-deficient (IL-21R−/−) K/BxN mice and found that these mice were completely refractory to the development of spontaneous arthritis. They contained fewer CD4+ T cells with a reduced proportion of homeostatically proliferating cells, fewer follicular Th cells, and, surprisingly, more Th17 cells than their control counterparts. They also failed to develop IgG1+ memory B cells and autoantigen-specific IgG1 Ab-secreting cells. IL-21 induced expression of receptor activator of NF-κB ligand (RANKL) a regulator of osteoclastogenesis, and few RANKL-expressing infiltrates were found in the synovia of IL-21R−/− K/BxN mice. Thus, our results demonstrate that IL-21 forms a positive feedback autocrine loop involving homeostatically activated CD4+ cells and that it plays an essential role in the development of autoimmune arthritis by mechanisms dependent on follicular Th cell development, autoreactive B cell maturation, and RANKL induction but independent of Th17 cell function. Consistent with this, in vivo administration of soluble the IL-21R-Fc fusion protein delayed the onset and progression of arthritis. Our findings suggest that effective targeting of IL-21-mediated processes may be useful in treating autoimmune arthritis.
Foxp3+ regulatory T cells (Tregs) are crucial for maintaining T cell tolerance, but their role in humoral autoimmunity remains unclear. To address this, we combined a model of autoantibody-dependent arthritis (K/BxN) with Foxp3 mutant scurfy mice to generate Treg-deficient K/BxN mice, referred to as K/BxNsf mice. The disease symptoms of K/BxNsf mice were exacerbated, and this coincided with increases in extrafollicular Th cells, follicular Th cells, and germinal centers. Surprisingly, the K/BxNsf mice exhibited an abnormal accumulation of mature plasma cells in their spleens and a corresponding loss of bone marrow plasma cells. The plasma cells were unresponsive to the bone marrow homing chemokine CXCL12, despite normal expression of the chemokine receptor CXCR4. Importantly, they were long-lived and less susceptible to the cytotoxic action of cyclophosphamide. They also expressed less FcγRIIb and were less apoptotic in response to autoantigen–autoantibody immune complexes. This suggests that Tregs control plasma cell susceptibility to cell death induced by engagement of FcγRIIb with immune complexes. Direct cytotoxic effects of Tregs also contribute to the death of plasma cells. Thus, our results reveal that Tregs suppress the emergence of long-lived splenic plasma cells by affecting plasma cell-autonomous mechanisms as well as T cell help, thereby avoiding the persistence of humoral autoimmunity.
Regulatory T (Tr) cells have been shown to arise in the periphery during induction of peripheral tolerance. However, the mechanism involved remains elusive. In the present study, we investigated the potential role of transforming growth factor (TGF)-beta in the peripheral induction of regulatory phenotypes in the conventional CD4(+)CD25(-) T cells. Upon priming in the presence of TGF-beta, there was greatly enhanced expression of CD25, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and the natural Tr cell-specific transcription factor Foxp3 in naive CD4(+)CD25(-) T cells. The CD25(+) cells that emerged later only in the TGF-beta-treated culture failed to express CD69, so distinguishing this population from activated CD25(+) effector cells. The TGF-beta-treated T cells entered an anergic state following restimulation, as judged by enhanced induction of programmed death (PD)-1, as well as impaired responses in terms of proliferation and IL-2 production. Importantly, the TGF-beta-costimulated CD4(+)CD25(-) T cells, prior to conversion to CD25(+) cells, were able to suppress the proliferation of responder T cells via contact-dependent and interleukin-10-independent mechanisms. Taken together, these results demonstrate that the existence of TGF-beta during early phase of priming is sufficient to induce CD4(+)CD25(-) Tr cells with anergic and immunoregulatory activities equivalent to thymus-derived CD4(+)CD25(+) Tr cells, and these cells are programmed to be CD25(+) cells under the prolonged resting conditions. Thus, our findings provide a novel mechanism by which TGF-beta mediates infectious tolerance in the periphery.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to components of the cell nucleus. These autoantibodies are predominantly produced with the help of follicular helper T (Tfh) cells and form immune complexes that trigger widespread inflammatory damage, including nephritis. In recent studies, mesenchymal stem cells (MSCs) elicited diverse, even opposing, effects in experimental and clinical SLE. Here we investigated the effect of human bone marrow-derived MSCs (hBM-MSCs) in a murine model of SLE, the F1 hybrid between New Zealand Black and New Zealand White strains (NZB/W). We found that infusion of female NZB/W mice with hBM-MSCs attenuated glomerulonephritis; it also decreased levels of autoantibodies and the incidence of proteinuria and improved survival. These effects coincided with a decrease in Tfh cells and downstream components. Infiltration of long-lived plasma cells into the inflamed kidney was also reduced in the hBM-MSC-treated mice. Importantly, hBM-MSCs directly suppressed the in vitro differentiation of naive CD4(+) T cells toward Tfh cells in a contact-dependent manner. These results suggest that MSCs attenuate lupus nephritis by suppressing the development of Tfh cells and the subsequent activation of humoral immune components. They thus reveal a novel mechanism by which MSCs regulate humoral autoimmune diseases such as SLE.
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