Electronic Poster | Session 2

080 – B cells regulate CD8+ MAIT cell effector functions: implications for multiple sclerosis

Ayman Rezk (1, 2, 4) – Koji Shinoda (1, 2) – Rui Li (1, 2) – Amit Bar-Or (1, 2, 3, 4)
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, PA, USA (1) – Center for Neuroinflammation and Experimental Therapeutics, University of Pennsylvania, PA, USA (2) – Division of Neurology, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, PA, USA (3) – Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada (4)

Anti-CD20 antibodies target and deplete a broad range of B cells (and a small subset of CD20-expressing T cells), substantially reducing new disease activity in multiple sclerosis (MS). Recent work has demonstrated important bi-directional interactions between B cells and CD4+ T cells that contribute to their abnormal immune responses in MS. This is supported by the observation that B-cell depletion attenuates CD4+ T cell responses in patients with MS. Curiously, B-cell depletion was noted to also attenuate CD8+ T cell responses in the same patients, suggesting a possible role for B cell:CD8+ T cell interactions in vivo. Though relatively less studied than CD4+ T cells, CD8+ T cells are strongly implicated in the inflamed MS central nervous system (CNS), with presence at sites of inflammation and injury of both CD8+ mucosal associated invariant T (MAIT) cells, and non-MAIT (conventional) CD8+ T cells. Here we set out to study potential interactions between B cells and both MAIT and conventional CD8+ T cells. We found that, in vitro, human B cells can suppress the proliferation of conventional CD8+ T cells yet significantly promote MAIT cell expansion. This differential B cell effect on the CD8+ T cell subsets was rather dependent on the differentiation stage of the B cells. B cells also differentially enhanced CD8+ T-cell subset cytotoxicity, an effect that did not require cell: cell contact, as it could be mediated through B-cell secreted products. B cells also modulated cytokine production in CD8+ T cells, by selectively enhancing IFN-γ production in MAIT cells, and suppressing GM-CSF and TNF production in non-MAIT cells. Further, anti-CD20 treatment resulted in an in vivo shift in the profile of circulating CD8+ T cells, including a reduction in MAIT cells, and diminished CD8+ T cell pro-inflammatory cytokine production, that in part mirrored our in vitro findings. Together this data indicates that disease-relevant cross-talk may exist between B cells and CD8+ T cells, including the capacity of B cells to reciprocally impact distinct CD8+ T cell subsets. The particular capacity of B cells to induce activation and effector responses of MAIT cells may be particularly relevant to MS pathophysiology and possibly to the therapeutic mode of action of anti-CD20 therapy.