B Cells Selectively Induce CD8+ MAIT Cell Effector Functions: Implications for Multiple Sclerosis (5355)

Objective: To study potential disease-relevant interactions between B cells and both CD8 MAIT and non-MAIT T cells in multiple sclerosis (MS) Background: B-cell depletion with anti-CD20 antibodies is highly effective in limiting new MS relapses, in part attributed to attenuation of CD4 T-cell responses, reflecting the well-recognized disease-implicated interactions between B cells and CD4 T cells. Curiously, B-cell depletion also attenuates CD8 T-cell responses, suggesting a role for B cell:CD8 T cell interactions in vivo. Both mucosal associated invariant T (MAIT) CD8 and non-MAIT (conventional) CD8 T cells have been implicated in MS. Design/Methods: Effects of differentially-activated B cells on CD8 T-cell subsets were initially assessed using in vitro co-cultures within whole peripheral blood mononuclear cells (PBMC) and using purified cell subsets from healthy controls. T cell proliferation, cytotoxicity and cytokine production were assessed by multiparametric flow-cytometry. Validated flow cytometry panels were applied in batch to cryopreserved PBMC from treatment-naive MS patients prior to and after in vivo anti-CD20 antibody therapy. Results: B cells suppress proliferation of non-MAIT CD8+ T cells yet significantly promote MAIT cell expansion in vitro. The differential impact on CD8+ T cell subsets is influenced by the B cell differentiation stage and mediated by B-cell secreted products. B cells also differentially impact CD8+ T-cell subset cytotoxicity and pro-inflammatory cytokine responses. In vivo, treatment with anti-CD20 selectively reduces frequencies and pro-inflammatory responses of MAIT cells, including diminished proliferation, cytotoxicity and pro-inflammatory cytokine production, that mirrors in vitro findings. Conclusions: Our findings implicate disease-relevant in vivo interactions between B cells and CD8+ T cells in MS. B cells differentially impact distinct CD8+ T cell subsets, selectively inducing of multiple effector responses of CD8+ MAIT cells. Selective decreases in CD8+ MAIT cell pro-inflammatory functions may contribute to the therapeutic mode of action of anti-CD20 therapy. Disclosure: Dr. Rezk has nothing to disclose. Dr. Shinoda has nothing to disclose. Dr. Li has nothing to disclose. Amit Bar-Or has participated as a speaker in meetings sponsored by, and received consulting fees from, Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, Janssen/Actelion, MAPI, MedImmune, Merck/EMD Serono, Novartis and Sanofi-Genzyme. Grant support from Janssen/Actelion, Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Roche/Genentech, MAPI, MedImmune, Merck/EMD Serono, Novartis and Sanofi-Genzyme.