Immunosuppression-resistant alloreactive memory CD4 T cells induce robust responses against organ transplants. In murine heart allograft recipients donor-reactive memory CD4 T cells provide help for the activation of effector CD8 T cells and alloantibody (alloAb) production independently of CD40/CD154 pathway. We demonstrated that memory CD4 T cells cause renal allograft rejection primarily through induction of pathogenic alloAb rather than through providing help for effector CD8 T cells. The goal of this study was to determine the co-stimulatory requirements for memory T cell helper functions and the development of acute alloAb mediated rejection of murine renal allografts. Non-sensitized B6 (H-2^b) recipients spontaneously accept A/J (H-2^a) renal allografts for more than 60 days with minimal anti-donor T cell and alloAb responses. Donor-reactive memory CD4 T cells were isolated from A/J skin-sensitized B6 mice and injected in naive B6 recipients followed by A/J kidney transplantation. First we tested whether alloreactive memory CD4 T cells can provide help for CD40 deficient B cells. Non-sensitized B6.CD40-/- mice accepted A/J renal allografts for more than 30 days and did not produce anti-donor IgG alloAb. B6.WT recipients injected with donor-reactive memory CD4 T cells rapidly developed high serum titers of anti-donor IgG alloAb and rejected A/J renal allografts (MST=7 d.) While memory CD4 T cells transferred into B6.CD40-/- recipients induced only intermediate titers of anti-donor IgG alloAb, these responses were sufficient to induce renal allograft rejection by d. 6 posttransplant. The rejecting grafts had minimal numbers of CD3⁺ T cell, intense macrophage infiltrate and diffuse C4d deposition in capillaries, typical of antibody-mediated injury. In parallel experiments, B6.WT mice containing memory CD4 T cells were treated with anti-CD154 mAb (MR1) one day prior to kidney allograft transplantation. In contrast to heart allograft rejection model, anti-CD154 mAb treatment significantly inhibited the generation of anti-donor IgG alloAb and prolonged renal allograft survival in recipients containing memory CD4 T cells (MST=44 d). Histological evaluation of the allograft tissue in these recipients at the time of rejection revealed low level of Cd4 deposition and signs of chronic glomerular injury. Taken together, our findings demonstrate that helper functions of memory CD4 T cells and their co-stimulatory requirements may depend on allograft type and immunogenicity.

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