Batf belongs to the activator protein 1 superfamily of basic leucine zipper transcription factors that includes Fos, Jun, and Atf proteins. Batf is expressed in mouse T and B lymphocytes, although the importance of Batf to the function of these lineages has not been fully investigated. We generated mice (BatfΔZ/ΔZ) in which Batf protein is not produced. BatfΔZ/ΔZ mice contain normal numbers of B cells but show reduced numbers of peripheral CD4+ T cells. Analysis of CD4+ T helper (Th) cell subsets in BatfΔZ/ΔZ mice demonstrated that Batf is required for the development of functional Th type 17 (Th17), Th2, and follicular Th (Tfh) cells. In response to antigen immunization, germinal centers were absent in BatfΔZ/ΔZ mice and the maturation of Ig-secreting B cells was impaired. Although adoptive transfer experiments confirmed that this B cell phenotype can be driven by defects in the BatfΔZ/ΔZ CD4+ T cell compartment, stimulation of BatfΔZ/ΔZ B cells in vitro, or by a T cell–independent antigen in vivo, resulted in proliferation but not class-switch recombination. We conclude that loss of Batf disrupts multiple components of the lymphocyte communication network that are required for a robust immune response.

Migration and trafficking receptors of Th17 cells to mucosal tissues have been unclear. We report that Th17 cells preferentially migrate to the intestine and associated-lymphoid tissues, and CCR6 is the homing receptor important for Th17 cell migration to certain tissue microenvironments of the intestine such as Peyer’s patches and other sites where its ligand CCL20 is expressed. We found the cytokine TGF-β1 is required for CCR6 expression while IL-2 suppresses it. CCR6-deficient Th17 cells aberrantly migrate to different compartments of the intestine. Surprisingly, administration of CCR6-deficient Th17 cells into SCID mice led to excessive intestinal inflammation with increased Th1 but decreased Th17 cells and FoxP3+ T cells. In addition, CCR6 deficiency led to aberrantly wide-spread effector T cells in the inflamed intestine of the SCID mice. We conclude that CCR6 regulates Th17 cell migration to the gut and effector T cell balance/distribution in inflamed intestine.

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Background & Aims-Retinoic acid plays a positive role in induction of FoxP3 + regulatory T cells. Because retinoic acid is produced as a metabolite of vitamin A in the intestine and FoxP3 + T cells regulate intestinal inflammation, we investigated the impact of vitamin A status on the regulatory T cells and inflammation in the intestine.

Induction of gut-homing receptors in T cells in response to retinoic acid requires the transcription factor BATF.

Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with clodronate inhibited the development of colitis, while the absence of IL10R specifically on macrophages sensitized infant mice to the development of colitis. These results indicate that IL10R-mediated regulation of macrophage function during the early postnatal period is indispensable for preventing the development of murine colitis.DOI: http://dx.doi.org/10.7554/eLife.27652.001

BackgroundIt is well established that PD-1 is expressed by follicular T cells but its function in regulation of human T helper cells has been unclear. We investigated the expression modality and function of PD-1 expressed by human T cells specialized in helping B cells.ResultsWe found that PD-1-expressing T cells are heterogeneous in PD-1 expression. We identified three different PD-1-expressing memory T cell subsets (i.e. PD-1low (+), PD-1medium (++), and PD-1high (+++) cells). PD-1+++ T cells expressed CXCR5 and CXCR4 and were localized in the rim of germinal centers. PD-1+ or PD-1++ cells expressed CCR7 and were present mainly in the T cell area or other parts of the B cell follicles. Utilizing a novel antigen density-dependent magnetic sorting (ADD-MS) method, we isolated the three T cell subsets for functional characterization. The germinal center-located PD-1+++ T cells were most efficient in helping B cells and in producing IL-21 and CXCL13. Other PD-1-expressing T cells, enriched with Th1 and Th17 cells, were less efficient than PD-1+++ T cells in these capacities. PD-1+++ T cells highly expressed Ki-67 and therefore appear active in cell activation and proliferation in vivo. IL-2 is a cytokine important for proliferation and survival of the PD-1+++ T cells. In contrast, IL-21, while a major effector cytokine produced by the PD-1-expressing T helper cells, had no function in generation, survival, or proliferation of the PD-1-expressing helper T cells at least in vitro. PD-1 triggering has a suppressive effect on the proliferation and B cell-helping function of PD-1+++ germinal center T cells.ConclusionOur results revealed the phenotype and effector function of PD-1-expressing T helper cell subsets and indicate that PD-1 restrains the B cell-helping function of germinal center-localized T cells to prevent excessive antibody response.

FoxP3+ T cells populate tumors and regulate anti-tumor immunity. The requirement for optimal population of FoxP3+ regulatory T cells in tumors remains unclear. We investigated the migration requirement and stability of tumor-associated FoxP3+ T cells. We found that only memory, but not naïve, FoxP3+ T cells are highly enriched in tumors. Almost all of the tumor-infiltrating FoxP3+ T cells express Helios, an antigen associated either with thymus-generated FoxP3+ T cells or activated T cells in the periphery. The tumor-infiltrating FoxP3+ T cells largely lack CD62L and CCR7, two trafficking receptors required for T cell migration into secondary lymphoid tissues. Instead, the tumor infiltrating FoxP3+ T cells highly express memory/tumor-associated CCR8 and CXCR4. Antigen priming is required for induction of this trafficking receptor phenotype in FoxP3+ T cells and only antigen primed, but not antigen-inexperienced naive, FoxP3+ T cells can efficiently migrate into tumors. While the migration of FoxP3+ T cells into tumors was a readily detectable event, generation of induced FoxP3+ T cells within tumors was unexpectedly inefficient. Genetic marking of current and ex-FoxP3+ T cells revealed that tumor-infiltrating FoxP3+ T cells are highly stable and do not readily convert back to FoxP3− T cells. Taken together, our results indicate that population of tumors with thymus-generated FoxP3+ T cells requires an antigen priming-dependent trafficking receptor switch in lymphoid tissues.