*Purpose: In transplantation, recipient CD4+ T cells have two potential means of MHC class II-restricted donor antigen detection: (1) the direct recognition of allogeneic MHC class II expressed by donor antigen-presenting cells (APCs) and (2) the indirect recognition of donor antigens processed and presented by recipient APCs. Importantly, indirect CD4 T cells are essential helper cells for generating aa donor-specific antibody (DSA) response. DSA in turn can contribute to chronic graft injury. A clear role of direct CD4+ T cells as effector cells has been shown in acute rejection, however, the role of indirect CD4+ T cells in chronic rejection is less clear. The function of NK cells in solid organ transplantation is multifaceted, but they have been implicated in several different animal models of chronic rejection. Our study sought to test the hypothesis that indirect CD4 T cells can contribute to NK-dependent allograft vasculopathy (CAV) even in the absence of DSA.

*Methods: We utilized a reductionist mouse model of cardiac transplantation with C57Bl/6 (B6) MHC class II-deficient (C2D) (H-2^b) hearts engrafted into immune-deficient BALB/c rag1^-/- (H-2^d) recipients (because CD4 T cell cannot acutely reject heart allografts without donor MHC II expression) . Recipients had no functional adaptive immunity but an intact innate immune system. After transplantation, the recipients received purified polyclonal BALB/c CD4+ T cells with or without concurrent administration of an NK cell depleting antibody (anti-Asialo GM1). Donor CAV determined by morphometric analysis of vascular occlusion and cellular recipient spleen composition were subsequently 30 days post CD4 T cell transfer.

*Results: Purified B6 CD4 T cells failed to acutely reject MHC class II-deficient heart allografts in BALBrag1^-/- recipients. Only 1/9 (11%) of allografts from un-reconstituted recipients developed any evidence of CAV while 5/7 (72%) of allografts from recipients receiving purified CD4+ T cels showed significant disease (p less than 0.05). Administration of anti-Asialo GM1 led to near complete elimination of host splenic NK cells and this depletion of NK cells was found to abrogate the development of CAV triggered by CD4+ T cells in 4/4 recipients.

*Conclusions: Indirect CD4 T cells are clearly linked to the generation of DSA. Results indicate that such CD4+ T cell reactivity can contribute to NK cell-dependent CAV, even in the absence of CD8+ T cell and B cell responses. As such, this represents an alternate form of CAV that can be antibody independent.

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