The Innate NK Cells, Allograft Rejection, and a Key Role for IL-15

Abstract

Transplant rejection is mediated primarily by adaptive immune cells such as T cells and B cells. The T and B cells are also responsible for the specificity and memory of the rejection response. However, destruction of allografts involves many other cell types including cells in the innate immune system. As the innate immune cells do not express germline-encoded cell surface receptors that directly recognize foreign Ags, these cells are thought to be recruited by T cells to participate in the rejection response. In this study, we examined the alloreactivity of the innate NK cells in Rag−/− mice using a stringent skin transplant model and found that NK cells at a resting state readily reject allogeneic cells, but not the skin allografts. We also found that IL-15, when preconjugated to its high affinity IL-15Rα-chain, is remarkably potent in stimulating NK cells in vivo, and NK cells stimulated by IL-15 express an activated phenotype and are surprisingly potent in mediating acute skin allograft rejection in the absence of any adaptive immune cells. Furthermore, NK cell-mediated graft rejection does not show features of memory responses. Our data demonstrate that NK cells are potent alloreactive cells when fully activated and differentiated under certain conditions. This finding may have important clinical implications in models of transplantation and autoimmunity.

KLRG1+ NK Cells Protect T-bet–Deficient Mice from Pulmonary Metastatic Colorectal Carcinoma

“…In particular, because IL-15 plays a key role in the development, survival, homeostasis, proliferation, and maturation of NK cells and cytotoxic T cells (Tc cells) (30)(31)(32)(33)(34)(35), it has therapeutic promise for anticancer immunotherapy (36). The systemic use of IL-15 was shown to prolong the survival of mice with metastatic CRC and other tumors through activation of Tc cells and NK cells (37)(38)(39)(40)(41).…”

Role of innate immunity in tolerance induction

“…В модели, включающей родительский по отношению к F1-потомку трансплантат сердца, CAV развивалась в трансплантатах сердца по НК и IFN-g зависимым механизмам [164], подчёркивая тем самым роль НК в патогенезе хронического отторжения трансплантата. В дополнение к содействию в отторжении, опосредованном Т-клетками, НК прямо ответственны за отторжение трансплантата в некоторых животных моделях [5,165,166]. Парадоксально, что, несмотря на вышеизложенные данные, указывающие на роль НК в отторжении, в некоторых животных моделях они также принимают Долгих участие в иммунной регуляции и необходимы для установления толерантности аллотрансплантата.…”

Fundamental Immunology of Skin Transplantation and Key Strategies for Tolerance Induction

“…In the conventional theory, NK cells participate in transplantation rejection as effector cells, which can mediate cytolytic effects against allogeneic and xenogeneic cells via the antibody-dependent cell-mediated cytotoxicity mechanism (Kumagai-Braesch et al 1998) and produce a variety of proinflammatory cytokines that promote the maturation of APCs and indirectly amplify T cell activation (Kroemer et al 2008a). Kroemer et al (2008b) reported that NK cells could reject skin allografts when stimulated with interleukin (IL)-15 in the absence of adaptive immune cells. However, recent studies have demonstrated that NK cells can kill allogeneic graft-derived APCs and prolong the survival of skin grafts through the inhibition of direct T cell priming or the elimination of activated alloreactive T cells in a perforin-dependent mechanism (Beilke et al 2005;Yu et al 2006).…”