Role of TIM Molecules in Regulatory and Inflammatory B cells in Allo andAutoimmunity

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In addition to humoral immunity, B cells play an important role shaping T effector responses through antigen presentation, costimulation, and cytokine production. Thus, B cell depletion ameliorates autoimmune diabetes and arthritis in mice, and rapidly improves RA and MS in humans, and outcomes do not correlate with fall in autoantibodies. In contrast, in both humans and mice, B cell depletion can also worsen autoimmunity, and can promote acute rejection and chronic vasculopathy in renal and cardiac transplant patients, respectively. These studies indicate that B cells can either enhance, or inhibit, inflammatory responses. In this regard, transfer of various B cell subsets can inhibit autoimmunity and allograft rejection through IL-10, and a growing list of other mechanisms. However, lack of a universal phenotype or master transcription factor (TF) for these Bregs has stymied the field. It is unknown whether these disparate cells are distinct or inter-related, or what regulates their differentiation or cytokine expression. Our preliminary data show that: 1) TIM-1 is an inclusive marker for IL-10+ Bregs. 2) Intact TIM-1 signaling on B cells regulates the expression of both TFs and various regulatory molecules (“regulatory module”). This allows us to test their role in Breg differentiation and function. 3) We also show that CpG-activated Pro-B cells transfer exceeding potent suppression, mediated by mature Breg progeny exhibiting different mechanisms of action in different locations. Both progenitors and progeny are TIM-1+, which allows us to examine the role of TIM-1 and TFs in Breg differentiation and regulatory module expression. B cells can also express various proinflammatory cytokines in autoimmune and infectious settings that strongly promote inflammatory responses. No phenotype for such effector B cells (Beff) has been established, and it is unclear whether the various cells described, are distinct or inter-related. Major aspects of Beff biology are completely unknown, including how differentiation and cytokine expression are regulated. We have discovered that: 1) TIM-4 identifies Beff that express IFNγ and IL-17 and accelerate allograft rejection. 2) IL-17 is notably, both a potent effector cytokine, and is also required for development of the Beff inflammatory program. Loss of B cell IL-17 not only reverses their inflammatory role, but also, inhibits the immune response, promoting allograft tolerance. 3) TIM-4 ligation inhibits proinflammatory cytokine expression. Based on our novel preliminary data, this PPG will utilize autoimmune and allograft models to test the central hypothesis that TIM-1 and TIM-4, respectively, are unifying markers for Bregs and Beff and regulate expression of TFs and other molecules important for their development and function. This will be addressed in 3 interactive and mutually supportive projects: Project 1: Role of Tim-1 and Bregs in Tolerance and Auto- immunity; Project 2: Immunoregulation by TLR-activated TIM-1+ ProB Cells in Transplantation; and Project 3: Inflammatory B Cells Defined by TIM-4 in the Alloimmune Response. This understanding is key to developing clinically relevant approaches to selectively target Beff and Bregs to enhance or inhibit the immune response.