Based on the protective effect of PD-L1-Fc against DSS-induced and T-cell-induced colitis, our results suggest that PD-1-mediated inhibitory signals have a crucial role in limiting the development of colonic inflammation. This implicates that PD-L1-Fc may provide a novel therapeutic approach to treat inflammatory bowel disease.

Interleukin-7 (IL-7) is a heavily glycosylated cytokine with a molecular mass of 25 kDa, and it is a member of the common ␥-chain receptor (CD132) cytokine family. IL-7 is secreted mainly by nonhematopoietic cells, such as thymic and intestinal epithelial cells, bone marrow stromal cells, keratinocytes, and reticular cells (1, 2). The receptor for IL-7, comprised of IL-7 receptor alpha (IL-7R␣; CD127) and the common ␥ chain, is expressed on various immune cells, including immature B cells, early thymocyte progenitors, and most mature T lymphocytes. IL-7 plays a role in the development of T cells, B cells, certain subsets of NK cells, and dendritic cells (DCs), as well as in the homeostasis of naive and memory T cells. In addition, IL-7 is important for ␥␦ T cell proliferation and NKT cell maintenance. However, the role of IL-7 in the differentiation of T follicular helper (Tfh) cells and the induction of humoral immunity remains unclear.Tfh cells are the unique CD4 ϩ T helper (Th) cells that provide cognate help to B cells to induce high-affinity antibody production in germinal centers (GCs) (3). GCs are specialized structures that develop within B cell follicles of secondary lymphoid tissues. GCs support intense B cell clonal expansion, somatic hypermutation, selection of high-affinity B cells, and class switching of immunoglobulin genes. These B cells ultimately are differentiated into both memory B cells and long-lived plasma cells that secrete high-affinity antibodies (2, 4).The differentiation of Tfh cells depends on the expression of a master transcriptional repressor, Bcl-6, which inhibits non-Tfh lineage differentiation (Th1, Th2, and Th17) by repressing Blimp-1 (5). Tfh cells express CXCR5 and a number of costimulatory molecules, such as ICOS and PD-1 (6). In addition, IL-6 and IL-21 have been shown to be important soluble regulators for the differentiation of Tfh cells (7-9). Recently, IL-27 was shown to increase the Tfh cell differentiation by upregulating IL-21 production (10). However, there have been conflicting reports that the absence of either IL-6 or IL-21 exhibits significant, moderate, or minimal effects on Tfh cell differentiation. The absence of both cytokines resulted in a more significant decrease in Tfh cell generation than each cytokine alone in vivo (11), indicating that IL-6 and IL-21 have redundant and/or additive functions in Tfh differentiation. It remains to be determined whether exogenous IL-6 or IL-21 induces the expansion of Tfh cells, as previous findings mentioned above were based on the experiments using knockout mice and/or blockade antibodies. Moreover, the generation of Tfh cells is not completely impaired even in the absence of IL-6 and IL-21 (11). These results indicate that these

Purpose: Durable complete remission of metastatic renal cell carcinoma (RCC) has rarely been achieved with current treatment modalities. To solve this problem, alternative therapeutic options with high efficacy and minimal side effects are strongly needed.Experimental Design: Mesenchymal stem cells (MSC) were engineered to coexpress dodecameric TRAIL and herpes simplex virus thymidine kinase (MSC/dTRAIL-TK). The antitumor effects of MSCs expressing dTRAIL (MSC/dTRAIL) or HSV-TK alone (MSC/TK) and MSC/dTRAIL-TK were compared with murine RCC cells using in vitro coculture system and in vivo experimental lung metastasis model. The effects of different doses and schedules of engineered MSCs on mice survival were also evaluated.Results: MSC/dTRAIL-TK exerted stronger apoptotic response in Renca cells than did MSC/TK or MSC/ dTRAIL after ganciclovir (GCV) treatment. In vivo imaging results suggest that MSCs reside longer in the lungs of metastatic tumor-bearing mice, compared with that of control mice, regardless of genetic engineering. In addition, MSC/dTRAIL-TK treatment followed by ganciclovir administrations significantly decreased the number of tumor nodules in the lung, to a greater degree than MSC/dTRAIL or MSC/TK, and led to a prolonged survival. More importantly, the antimetastatic effect of MSC/dTRAIL-TK was markedly enhanced by repeated injections but not by increased dose, and resulted in 100% survival of tumor-bearing mice after three injections.Conclusion: Sequential combination gene therapy using MSC/dTRAIL-TK achieved long-term remission of metastatic RCC without noticeable toxicity. Our findings provide an innovative therapeutic approach to completely eradicate metastatic tumors by simple, repeated administrations of MSC/dTRAIL-TK.