B cells perform important immunological functions. Beyond their unique role in humoral immunity, B cells can serve as APCs, provide co-stimulation, and produce cytokines that affect Th responses. B cells, much like T cells, give rise to polarized subsets, termed Be1, Be2 and Breg that produce specific cytokines such as IFNΓ, IL-4 and IL-10, respectively. Identifying markers that could distinguish between these subsets would be of paramount importance in targeting specific subsets for therapeutic expansion or deletion suitable to specific immunological conditions. We reported that TIM-1 is an inclusive marker for B cells expressing IL-4 (Be2 cells) and IL-10 (Breg). TIM-1+ Be2 cells augmented IL-4 by Th2 cells, and IL-4 was essential for generation of Breg which could transfer allograft tolerance. We now show that TIM-4, a TIM-1 ligand expressed by APCs, is also expressed by a subset of B cells. TIM-4 is expressed by ∼6% of B cells, increasing to 10% after immunization- levels very similar to TIM-1 on B cells. However, FACs analysis reveals that TIM-1 and TIM-4 are expressed on largely distinct subpopulations. Whereas <1% of total B cells express these cytokines, TIM-1+ B cells are enriched for IL-4 (6.5%) and IL-10 (14%) vs. IFNΓ (1%). In contrast, TIM-4+ B cells are enriched for IFNΓ (2.5%), compared to IL-4 (1%) and IL-10 (4%). Thus, TIM-1+ B cells are enriched for Be2 and Breg cells while TIM-4+ B cells are enriched for Be1 cells. Transfer of alloantigen primed TIM-1 and TIM-4 B cells to B cell deficient JhD allograft recipients, revealed that TIM-1 B cells increased IL-4+, IL-10+ and Foxp3+ T cells (1.2-1.7X) while decreasing IFNΓ+ T cells (1.4X) compared to JhD controls (no cell transfer), p<0.05 for each. In contrast, TIM-4 B cells enhanced IFN-Γ+ T cells (1.5X) while decreasing IL-4+, IL-10+ and Foxp3+ T cells (1.2-1.8X), p<0.05 for each. Whereas TIM-1 B cell transfer to JhD recipients significantly prolonged islet allograft survival (MST 70d), transfer of TIM-4+ B cells accelerated rejection (MST 11d) compared to controls (no cell transfer; MST 15d), p <0.05. In contrast, transfer of TIM-1+ B cells into ΜMT mice accelerated subcutaneous B16 melanoma tumor growth, vs. TIM-4+ B cells, which delayed tumor growth and prolonged survival (p<0.003). Therefore, TIM-1 and TIM-4 identify Be2/Breg and Be1 cells that can directly impact T cells responses. Importantly, TIM-1 and TIM-4 can be used as therapeutic targets to promote or dampen inflammatory responses.

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