CD28 Co-Stimulation Down Regulates Th17 Development

Abstract

Th17 cells are implicated in host defence and autoimmune diseases. CD28/B7 co-stimulation is involved in the induction and progression of autoimmune diseases, but its role in controlling murine Th17 cell fate remains to be clarified. We here report that soluble anti-CD28 mAb suppressed the differentiation of anti-CD3-stimulated naïve CD4+ T cells into IL-17-producing cells. CD28 co-stimulation reduced the frequency of proliferating cells that produce IL-17. We provide evidence for an IL-2 and IFN-γ-dependent mechanism of CD28-mediated IL-17 suppression. CD28 blockade of Th17 development was correlated with a decrease rather than an increase in the percentage of Foxp3+ T cells. In APC/T cell co-cultures, mature dendritic cells (DC) were less efficient than immature DC in their ability to support Th17 cell differentiation, while CTLA4-Ig, an agent blocking CD28/B7 and CTLA4/B7 interactions, facilitated both murine and human Th17 differentiation. This study identifies the importance of B7 co-stimulatory molecules in the negative regulation of Th17 development. These unexpected results caution targeting the CD28/B7 pathways in the treatment of human autoimmune diseases.

The NF-κB Transcription Factor c-Rel Is Required for Th17 Effector Cell Development in Experimental Autoimmune Encephalomyelitis

“…and Il21r 2/2 mice display normal Th17 development in culture and remain highly susceptible to EAE (35,36 (42). Our finding that Th17 development was negatively regulated by CD28 costimulation also supports a recent report by others (32). The use of CD28 costimulation in the culture may explain a recent study claiming that c-Rel did not regulate Th17 cell development (43).…”

“…2E) in both populations. In contrast, CD28 costimulation, which was recently shown to inhibit Th17 development (32) and also regulates IL-2 expression via c-Rel (33), repressed Th17 development in cultures of wild-type but not rel 2/2 CD4 + T cells (Fig. 2C, 2D), thereby establishing that CD28 but not IL-2 inhibition of Th17 differentiation is c-Rel dependent.…”

The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells

“…Malt1 -/-mice were originally generated in our laboratory (20,37) and backcrossed for more than 10 generations into the C57BL/6 backIn vitro, IL-6, IL-21, and IL-23 -with or without TGF-β -have been reported to induce Th17 cell differentiation or stabilization (5,11,12,44,45). However, the roles of TCR stimulation and costimulatory signaling in the differentiation of specific Th subsets have yet to be clearly delineated (46)(47)(48)(49). Engagement of both the TCR and CD28 results in activation of the IKK complex, which relieves NF-κB from its suppression by the IκB proteins.…”

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

“…Much of the work addressing this question has focused on the role of cytokines produced by APCs, leading to the conclusions that IL-12 initiates the Th1 response, whereas IL-6 and IL-23 are involved in generating Th17 responses (1)(2)(3). Additionally, the generation of Th1 and Th17 effector cells has been shown to be dependent on various other parameters including transcription factors, epigenetic modifications, and CD28 costimulation (2)(3)(4)(5). There is also evidence for temporal differences in the appearance of Th1 and Th17 cells, with most studies showing that the Th17 response peaks early, followed by the appearance of Th1 cells (6)(7)(8)(9).…”