Non-adaptive cellular immune responses as studied in euthymic and athymic nude rats

Summary The athymic nude (rnu) rat lacks a functional thymus and normal alloreactive T cells. These animals, therefore, have been widely used as tools for studying thymus-independent immune responses. The absence of functional T cells would, to most investigators, indicate that these rats have a defective cellular immune defence. However, although rnu rats accept organ allografts infinitely, they are nevertheless capable of rejecting allografts consisting of lymphocytes or bone marrow cells with increased vigour, and this via antibody-independent mechanisms. These rejection phenomena have operationally been termed allogeneic lymphocyte cytotoxicity (ALC) and allogeneic bone marrow cell cytotoxicity (ABC). Unlike organ allograft immunity this kind of rejection requires no presensitization of the recipient and is surprisingly rapid: it commences within a few hours of i.v. injection of the allogeneic cells and is usually complete by 24 h. Moreover, products coded for by genes within, or closely linked to the major histocompatibility complex (MHC), are clearly involved in the interaction between effector and target cells, as grafted cells from MHC-congenic rat strains are vigorously rejected.In contrast to the defective T cell immune responses in athymic nude rats, the natural killer (NK) cell function is not impaired, and it has been suggested that the spontaneous rejection of MHC-incompatible lymphohematopoietic cells is in fact mediated by NK cells. If the MHC antigens themselves serve as targets in this kind of allorejection, this hypothesis is in apparent contrast with the prevailing view that recognition by NK cells is not guided by, or directed against, MHC-antigens on the target cell surface.Ageing athymic nude mice and rats generate cells that rearrange and express T cell receptor (TCR) genes, and this has raised the possibility that T cells or T-like cells in athymic nude animals are responsible for ALC and ABC. This possibility urged the device of an in vitro test system for identification and further characterization of the effector cells in these rejection phenomena. Under appropriate conditions, cells from the rnu rat spleen or liver with natural killer function, i.e. the ability to lyse certain kinds of tumor cells in vitro, are also spontaneously cytotoxic for allogeneic small lymphocytes and bone marrow cells in vitro. Furthermore, these cells can be grown in vitro in the presence of interleukin 2 (IL-2) to generate populations of lymphokine-activated killer (LAK) cells, and these cells have the same spectrum of alloreactivity in ALC and ABC as the native NK cells. We have characterized these cells extensively for rearrangement and expression of TCR genes and expression of cell surface molecules characteristic of T cells and NK cells. All these data argue strongly against any role of T cells in ALC and ABC, but show that NK cells are involved. All these pieces of information have led to the novel idea that NK cells, the main effector cells within the non-adaptive immune system, in addition to their ability to recognize a wide range of tumor cells through ill-defined target antigens, also can recognize and kill normal hematopoietic cells through the recognition of MHC-incompatibilities. These observations raise the intriguing possibility that these two features of NK cells are closely related, or perhaps different manifestations of the same recognition mechanism. However, the biological function of a putative allorecognition system connected to NK cells is still the center of as much speculation as the biological significance of T cell alloaggression was some years ago. The deeper understanding of which biological functions of NK cells underly the phenomena of ABC and ALC must await the characterization of receptor molecules and target cell structures involved in these reactions.Abbreviations ABC allogeneic bone marrow cell cytotoxicity - ALC allogeneic lymphocyte cytotoxicity - ADCC antibody dependent cellular cytotoxicity - GVH graft-vs-host - Ig immunoglobulins - IL-2 interleukin-2 - IDC interdigitating cells - LAK cells Lymphokine activated killer cells - LGL Large granular lymphocytes - Mab monoclonal antibody - MHC major histocompatibility complex - NK cells natural killer cells - PBL periphered blood lymphocytes - TCR T cell receptor complex - T_h T helper cells - Tc T cytotoxic cells