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Antigen-presenting cells (APCs) integrate signals emanating from local pathology and program appropriate T cell responses. In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases damage-associated molecular patterns (DAMPs) that generate proinflammatory APCs that secrete IL-12, which is a driver of donor Th1 responses, causing graft-versus-host disease (GVHD). Nevertheless, other mechanisms exist to initiate alloreactive T cell responses, as recipients with disrupted DAMP signaling or lacking IL-12 develop GVHD. We established that tissue damage signals are perceived directly by donor [CD4.sup.+] T cells and promoted T cell expansion and differentiation. Specifically, the fibroblastic reticular cell-derived DAMP IL-33 is increased by recipient conditioning and is critical for the initial activation, proliferation, and differentiation of alloreactive Th1 cells. IL-33 stimulation of [CD4.sup.+] T cells was not required for lymphopenia-induced expansion, however. IL-33 promoted IL-12-independent expression of Tbet and generation of Th1 cells that infiltrated GVHD target tissues. Mechanistically, IL-33 augmented [CD4.sup.+] T cell TCR-associated signaling pathways in response to alloantigen. This enhanced T cell expansion and Th1 polarization, but inhibited the expression of regulatory molecules such as IL-10 and Foxp3. These data establish an unappreciated role for IL-33 as a costimulatory signal for donor Th1 generation after alloHCT., Introduction Allogeneic hematopoietic stem cell transplantation (alloHCT) is a curative therapy for high-risk hematopoietic malignancies and is also used to correct life-threatening lymphohematopoietic disorders. alloHCT has also shown promise as [...]

CD4 T follicular helper (TFH) cells interact with and stimulate the generation of antigen-specific B cells. TFH cell interaction with B cells correlates with production of SIV-specific immunoglobulins. However, the fate of TFH cells and their participation in SIV-induced antibody production is not well understood. We investigated the phenotype, function, location, and molecular signature of TFH cells in rhesus macaques. Similar to their human counterparts, TFH cells in rhesus macaques represented a heterogeneous population with respect to cytokine function. In a highly differentiated subpopulation of TFH cells, characterized by [CD150.sup.lo] expression, production of Th1 cytokines was compromised while IL-4 production was augmented, and cells exhibited decreased survival, cycling, and trafficking capacity. TFH cells exhibited a distinct gene profile that was markedly altered by SIV infection. TFH cells were infected by SIV; yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH cells was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. Therefore, chronic SIV does not disturb the ability of TFH cells to help B cell maturation and production of SIV-specific immunoglobulins., Introduction The generation of antigen-specific B cells is dependent upon their interaction with T follicular helper (TFH) cells in the B cell follicles of the LN and spleen (SP) (1), [...]

Effective B cell--mediated immunity and antibody responses often require help from [CD4.sup.+] T cells. It is thought that a distinct [CD4.sup.+] effector T cell subset, called T follicular helper cells ([T.sub.FH]), provides this help; however, the molecular requirements for [T.sub.FH] differentiation are unknown. We found that expression of the transcription factor Bcl6 in [CD4.sup.+] T cells is both necessary and sufficient for in vivo [T.sub.FH] differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp-1, an antagonist of Bcl6, inhibits [T.sub.FH] differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that [T.sub.FH] cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in [T.sub.FH] differentiation.