Role of Natural Killer Cell Subsets in Cardiac Allograft Rejection

Abstract

To achieve donor-specific immune tolerance to allogeneic organ transplants, it is imperative to understand the cell types involved in acute allograft rejection. In wild-type mice, CD4 + T cells are necessary and sufficient for acute rejection of cardiac allografts. However, when T-cell responses are suboptimal, such as in mice treated with costimulation-targeting agents or in CD28-deficient mice, and perhaps in transplanted patients taking immunosuppressive drugs, the participation of other lymphocytes such as CD8 + T cells and NK1.1 + cells becomes apparent. We found that host NK but not NKT cells were required for cardiac rejection. Ly49G2 + NK cells suppressed rejection, whereas a subset of NK cells lacking inhibitory Ly49 receptors for donor MHC class I molecules was sufficient to promote rejection. Notably, rejection was independent of the activating receptors Ly49D and NKG2D. Finally, our experiments supported a mechanism by which NK cells promote expansion and effector function of alloreactive T cells. Thus, therapies aimed at specific subsets of NK cells may facilitate transplantation tolerance in settings of impaired T-cell function.

The Activating Immunoreceptor NKG2D and Its Ligands Are Involved in Allograft Transplant Rejection

“…An unresolved question in our studies is whether the graft prolongation by anti-NKG2D Ab is mediated by NKG2D blockade on CD8 ϩ T cells, NK1.1 ϩ cells, or both. Within the NK1.1 ϩ population, it is likely that NKG2D blockade is most relevant for NK cells, as NKT cells have been shown to be dispensable for cardiac rejection in the Cd28 Ϫ/Ϫ model (26). Systems to distinguish the effects of anti-NKG2D mAb on NK cells vs T cells are not currently available.…”

The Innate Immune System in Allograft Rejection and Tolerance

“…Maier et al (79) demonstrated that in Cd28 Ϫ/Ϫ recipients, which have impaired ability to receive T cell costimulatory signals, specific depletion of NK cells prolongs survival of fully mismatched cardiac allografts. Using the same model, McNerney et al (80) show that NK cells promote the expansion and effector function of CD28-deficient alloreactive T cells by a mechanism independent of the NK cell-activating receptors Ly49D and NKG2D.…”

Role of innate immunity in tolerance induction

“…НК могут компенсировать отсутствие Т-клеточных костимулирующих сигналов и способствовать ускорению Т-клеточного ответа против трансплантата. В пользу этой потенциальной роли НК в помощи отторжению, опосредованному Т-клетками, свидетельствует наблюдение, что НК инфильтруются в трансплантат сердца раньше, чем Т-клетки, как у мышей, так и у людей [5,162,163]. Интересно, что инфильтрация эндомиокарда НК у пациентов с человеческими трансплантатами позволяет предсказать отторжение трансплантата сердца [163], предполагая далее вспомогательную роль НК в опосредованном Т-клетками отторжении трансплантата.…”

“…Вероятно, во время раннего аллогенного ответ а в игре находится более чем один механизм. Судьба и функции субпопуляций НК остаётся мало определённой, хотя некоторые исследовательские группы приводят аргументы в пользу того, что некоторые субпопуляции и НК-клеточные специфические рецепторы благоприятствуют толерантности против иммунитета [5,153,162].…”