The role of CD8+ T cells during allograft rejection

Brazilian Journal Medical and Biological Research (2002) 35: 1247-1258 + T cells CD8 andofgraft rejection ISSN 0100-879X Review 1247 The role of CD8+ T cells during allograft rejection V. Bueno and J.O.M. Pestana Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil Abstract Correspondence V. Bueno Disciplina de Nefrologia EPM, UNIFESP Rua Botucatu, 740 04023-900 São Paulo, SP Brasil Fax: +55-11-5573-9652 E-mail: Research supported by FAPESP (No. 98/13340-2). Received July 31, 2001 Accepted August 20, 2002 Organ transplantation can be considered as replacement therapy for patients with end-stage organ failure. The percent of one-year allograft survival has increased due, among other factors, to a better understanding of the rejection process and new immunosuppressive drugs. Immunosuppressive therapy used in transplantation prevents activation and proliferation of alloreactive T lymphocytes, although not fully preventing chronic rejection. Recognition by recipient T cells of alloantigens expressed by donor tissues initiates immune destruction of allogeneic transplants. However, there is controversy concerning the relative contribution of CD4+ and CD8+ T cells to allograft rejection. Some animal models indicate that there is an absolute requirement for CD4+ T cells in allogeneic rejection, whereas in others CD4-depleted mice reject certain types of allografts. Moreover, there is evidence that CD8+ T cells are more resistant to immunotherapy and tolerance induction protocols. An intense focal infiltration of mainly CD8+CTLA4+ T lymphocytes during kidney rejection has been described in patients. This suggests that CD8+ T cells could escape from immunosuppression and participate in the rejection process. Our group is primarily interested in the immune mechanisms involved in allograft rejection. Thus, we believe that a better understanding of the role of CD8+ T cells in allograft rejection could indicate new targets for immunotherapy in transplantation. Therefore, the objective of the present review was to focus on the role of the CD8+ T cell population in the rejection of allogeneic tissue. CD8 as a co-receptor/accessory molecule T lymphocytes can be separated into two subsets based on their expression of the CD4 and CD8 molecules on the cell surface. Approximately 65% of peripheral aß-positive T cells express CD4 and 35% express CD8. CD4+ T cells are restricted to major histocompatibility complex (MHC) class II and act as helper cells for various immune responses, whereas CD8+ T cells recognize antigens in the context of MHC class I and Key words · Transplantation · Rejection · T cells · Cytokines · Chemokines develop into cytotoxic effector cells. The present data support the view that T cell activation requires CD8 or CD4 and T cell receptor (TCR) binding to the same peptide/ MHC (pMHC) molecule, leading to the classification of these cells as co-receptors. CD8 is expressed on the cell surface in two forms: a CD8aß heterodimer and a CD8aa homodimer. CD8aß is the prevalent form on the surfaces of the T cell population and is believed to enhance cytotoxic T lymphocyte (CTL) activation better than CD8aa. CD8, either a or ß chain, consists of four discrete Braz J Med Biol Res 35(11) 2002 1248 V. Bueno and J.O.M. Pestana functional domains that can be related to the primary sequence as follows: the Ig-like ectodomains, the membrane proximal stalk region, the transmembrane domain, and the cytoplasmic domain. The extracellular Iglike domain is involved in the binding to MHC. The stalk region is flexible and highly glycosylated, a fact which is believed to be important in extending the region to reach the MHC, and is also postulated to interact with TCR. The cytoplasmic domain of CD8a consists of a p56lck binding motif important for signal transduction. CD8 enhances T cell recognition of pMHC on the surface of antigen-presenting cells (APC) since binding of CD8 and TCR to the same pMHC would increase the overall avidity between the surfaces of APC and T cells. Second, CD8 binding to pMHC recruits p56lck tyrosine kinase through its cytoplasmic domain into the T cell signaling complex and thus enhances signal transduction. Third, CD8 binding to pMHC possibly reduces the overall flexibility of pMHC on the cell surface, positioning the pMHC more favorably for TCR binding. It is more likely that CD8 is recruited to the pMHC-TCR complex by intracellular binding of the a chain-associated p56lck to TCR-associated ZAP-70. Once recruited, CD8 would enhance pMHC binding by adding to the much stronger TCR-pMHC interaction (1). The term accessory molecule has been used to describe the activities of CD4 and CD8 when they are unable to bind to the same MHC molecule as the TCR. There are conflicting data as to whether the binding of MHC molecules in an accessory manner contributes to T cell activation. However, Smith and Potter (2) showed that transgenic mouse skin grafts expressing a disparate class I molecule that does not engage CD8 are rejected as vigorously as wild-type grafts. Rejection was caused by a CD8+ class I reactive CTL, which required CD8 engagement for cytolysis and secretion of interferon g (IFN-g), although the co-engagement Braz J Med Biol Res 35(11) 2002 with the same MHC class I molecule as TCR was not necessary. As an accessory molecule, CD8 would increase the overall avidity of the T cell-target cell interaction, or transduce signals through p56lck that either act independently of or intersect downstream from TCR-mediated signal transduction. CD8+ T cells and allograft rejection The previous belief that CD8+ T cells are a homogenous population of CD4-dependent cells and produce a limited number of cytokines such as IFN-g, tumor necrosis factor a (TNF-a) and lymphotoxin has changed. It is now accepted that CD8+ T cells can polarize in the same way as CD4+ T cells into cytotoxic T (Tc) cells - Tc1 (IFN-g) and Tc2 (IL-4, IL-5) - and in some situations CD4independent responses by CD8+ T cells occur. CD8+ T cell helper independence might be related to the avidity of the interaction between TCR on these cells and the antigen presented by class I molecules on the APC. High avidity T cells (multiple interactions of TCR and CD8 molecules on the T cell with pMHC complexes on the APC) may receive a strong signal that induces both IL-2R and IL-2 synthesis resulting in a helper-independent response. CD8+ T cells with low avidity may induce IL-2R but produce little or no IL-2 and depend on IL-2 production by CD4+ T cells. Heath et al. (3), using transgenic mice expressing a specific TCR for H2Kb, showed that TCRhigh/CD8high cells tested against splenocytes expressing different densities of H-2Kb were competent IL-2 producers, whereas TCRlow/CD8low presented marginal or no levels of IL-2 in the same assay. Deeths et al. (4) showed that in vitro a helperindependent phase of the CD8+ T cell response is consistent w (...truncated)