NK Cells Delay Allograft Rejection in Lymphopenic Hosts by Downregulating the Homeostatic Proliferation of CD8+ T Cells

Abstract

T cells present in lymphopenic environments undergo spontaneous (homeostatic) proliferation resulting in expansion of the memory T cell pool. Homeostatically generated memory T cells protect the host against infection but can cause autoimmunity and allograft rejection. Therefore, understanding the mechanisms that regulate homeostatic T cell proliferation is germane to clinical settings in which lymphodepletion is used. In this study, we asked whether NK cells, which regulate immune responses in lymphocyte-replete hosts, also regulate homeostatic T cell proliferation under lymphopenic conditions. We found that T cells transferred into genetically lymphocyte-deficient RAG−/− mice proliferate faster and generate more CD8+ memory T cells if NK cells were absent. CD8+ T cells that underwent homeostatic proliferation in the presence of NK cells generated mostly effector memory (CD44highCD62Llow) lymphocytes, whereas those that divided in the absence of NK cells were skewed toward central memory (CD44highCD62Lhigh). The latter originated predominantly from proliferation of the “natural” central memory CD8+ T cell pool. Regulation of homeostatic proliferation by NK cells occurred independent of perforin but was reversed by excess IL-15. Importantly, NK depletion enhanced CD8+ T cell recovery in T cell-depleted wild-type mice and accelerated rejection of skin allografts, indicating that regulation of homeostatic proliferation by NK cells is not restricted to genetically lymphocyte-deficient animals. These results demonstrate that NK cells downregulate homeostatic CD8+ T cell proliferation in lymphopenic environments by competing for IL-15. Concomitant NK and T cell depletion may be undesirable in transplant recipients because of enhanced expansion of memory CD8+ T cells that increase the risk of rejection.

Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation

“…Similar results were observed in wild type mice depleted of both CD4/CD8 T cells compared to NK/T-cell depleted WT mice. 21 As opposed to Zecher et al, we could not prove that the removal of NK cells conferred an advantage to CD8 T cells to recover quicker and to a greater extent. In our transplant setting, CD8 T cells recovered after depletion to the same extent in NK sufficient as in NK-cell depleted mice, meaning that NK cell depletion did not alter the recovery of the total CD8 T cell numbers.…”

“…Our data in this sense is in agreement with that reported by Zecher´s work using immunodeficient and T cell-depleted immunocompetent recipients who provided evidence in favor of the role of NK cells in modulating CD8 T cell responses, not by killing homeostatically proliferating T cells, but by competing for T cell growth factors. 21 Our findings suggest that this competition for common resources may provide an advantage to NK cells that would reduce the availability of these cytokines to the alloreactive repertoire of CD8 T cell reacting against bm1 antigens. Therefore, reaching the threshold frequency of alloantigen specific CD8 T cells necessary to initiate rejection would take longer and consequently graft rejection would be delayed.…”

“…21 Moreover, the population of NK cells expressing low rather than high levels of CD27 has been shown to promote allograft survival by limiting the homeostatic proliferation and expansion of interferon-γ–producing memory CD8 + T cells under costimulatory blockade. 22 …”

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

“…CD8 1 memory effector T cells are known to restrict IL-15-dependent homeostasis of gd-T cells [49,50]. Furthermore, NK cells and CD8 1 T cells compete for IL-15 in lymphopenic mice [51]. Therefore, it is conceivable that CD8 1 T cells that represent the major T-cell population after transplantation also compete with NK cells for the elevated levels of IL-15 present in transplanted patients [27][28][29].…”

Role of innate immunity in tolerance induction

“…НК, продуцирующие IL-10, ингибируют антиген-специфическую Т-клеточную пролиферацию и продукцию цитокинов in vitro, и это отменяется блокадой рецептора IL-10 [168]. В модели мышей с аллотрансплантатами кожи гомеостатическую пролиферацию адаптивно трансфецированных T-клеток CD8 + ингибировали НК и истощение НК приводило к увеличению экспансии и ускорению отторжения трансплантата [169]. При трансплантации мышам островков экспрессия МНС 1 и НК, как было найдено, необходимы для индукции толерантности путем либо костимуляторной блокады, либо путём лечения с помощью анти-LFA-1.…”