Natural Killer Cells are Essential for Allograft Vasculopathy in a Model of CD4+ T Cell-Mediated Chronic Rejection

Abstract

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. As donor-derived APCs are gradually depleted over time, the indirect pathway emerges as the dominant mode of allorecognition in the long-term. 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 NK cells are the key effectors in sustaining an anti-donor response in a model of indirect CD4+ T cell mediated chronic allograft vasculopathy (CAV). Methods We utilized a mouse model of cardiac transplantation with MHC class II-deficient B6.C2D (H-2b) hearts engrafted into immune-deficient BALB/c.rag-/- (H-2d) recipients. 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). Allografts and recipient spleens were subsequently assessed after 30 days. Results All allografts demonstrated cardiac contraction, as detected by abdominal palpation, for 30 days both with and without CD4+ T cell reconstitution. Only 1/9 (11%) of allografts from un-reconstituted recipients demonstrated evidence of CAV, while 5/7 (72%) of allografts from recipients that received adoptively transferred CD4+ T cells showed disease (p Conclusion In the context of immunodeficient hosts, CD4+ T cells are sufficient to mediate chronic allograft vasculopathy, independent of recipient CD8+ T cell and B cell responses. Recipient NK cells are necessary for the development of this form of chronic rejection.