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Follicular helper T (Tfh) cells are essential for the formation of high affinity antibodies after vaccination or infection. Although the signals responsible for initiating Tfh differentiation from naïve T cells have been studied, the signals controlling sequential developmental stages culminating in optimal effector function are not well understood. Here we use fate mapping strategies for the cytokine IL-21 to uncover sequential developmental stages of Tfh differentiation including a progenitor-like stage, a fully developed effector stage and a post-effector Tfh stage that maintains transcriptional and epigenetic features without IL-21 production. We find that progression through these stages are controlled intrinsically by the transcription factor FoxP1 and extrinsically by follicular regulatory T cells. Through selective deletion of Tfh stages, we show that these cells control antibody dynamics during distinct stages of the germinal center reaction in response to a SARS-CoV-2 vaccine. Together, these studies demonstrate the sequential phases of Tfh development and how they promote humoral immunity.Follicular helper T cells play critical roles in the formation of high affinity antibody responses, but the signals involved in the development of these cells after initial differentiation are poorly understood. Here Podestà, Cavazzoni and colleagues characterise transitionary phases of follicular helper T cell development and how progression through these stages is linked to humoral immunity. [ABSTRACT FROM AUTHOR]

(E) mRNA expression of BTLA in the kidney graft by qRT-PCR among the Allo + NC and Allo + BTLA groups. (A) IHC staining showed significantly upregulated BTLA expression in the kidney tissue of the SD rat by BTLA-overexpression adenovirus (Normal + BTLA) compared with the negative control vector (Normal + NC) and normal SD rat (Normal). [Extracted from the article]

Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current immunosuppression protocols are not designed to target antigen-specific alloimmunity and are uncapable of preventing chronic allograft injury. As myeloid-derived suppressor cells (MDSCs) are potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2Kb, I-Ab) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2Kd, I-Ad) or third-party (C3H, H2Kk, I-Ak) cardiac grafts. Spleens and allografts from C57BL/6 recipients were harvested for immune phenotyping, transcriptomic profiling and functional assays. Single injection of donor-derived MDSCs significantly prolonged the fully MHC mismatched allogeneic cardiac graft survival in a donor-specific fashion. Transcriptomic analysis of allografts harvested from donor-derived MDSCs treated recipients showed down-regulated proinflammatory cytokines. Immune phenotyping showed that the donor MDSCs administration suppressed effector T cells in recipients. Interestingly, significant increase in recipient endogenous CD11b+Gr1+ MDSC population was observed in the group treated with donor-derived MDSCs compared to the control groups. Depletion of this endogenous MDSCs with anti-Gr1 antibody reversed donor MDSCs-mediated allograft protection. Furthermore, we observed that the allogeneic mixed lymphocytes reaction was suppressed in the presence of CD11b+Gr1+ MDSCs in a donor-specific manner. Donor-derived MDSCs prolong cardiac allograft survival in a donor-specific manner via induction of recipient's endogenous MDSCs. [ABSTRACT FROM AUTHOR]

Acute rejection is a major risk for renal transplant failure. During this adverse process, activated T cells are considered the main effectors. Recently, B and T lymphocyte attenuator (BTLA), a member of the CD28 family receptor, was reported to be a novel inhibitory regulator of T cell activation in heart and pancreatic allograft rejection. Due to the similarity of acute rejection pathways among different organs, we hypothesized that BTLA might play a role in acute rejection of kidney transplant. In renal transplant patients, we observed that BTLA expression was significantly decreased in peripheral CD3+ T lymphocytes of biopsy-proven acute rejection (BPAR) recipients compared with control patients with stable transplanted kidney functions. Remarkably, overexpression of BTLA in the rat model was found to significantly inhibit the process of acute rejection, regulate the postoperative immune status, and prolong allograft survival. BTLA overexpression significantly suppressed IL-2 and IFN-γ production and increased IL-4 and IL-10 production both in vivo and in vitro. Moreover, vital factors in T-cell signaling pathways, including mitogen-associated protein kinases (MAPK), nuclear factor-kappa B (NF-κB) and nuclear factor of activated T cells (NFAT), were also significantly repressed by BTLA overexpression. Therefore, BTLA can suppress acute rejection and regulate allogeneic responses of kidney transplant by regulating TCR downstream signals and inflammatory cytokines production to improve allografts outcomes. [ABSTRACT FROM AUTHOR]