A ZAP-70 kináz hiányának vizsgálata in vivo T-sejt aktivációban, differenciációban és autoimmun arthritis kialakulásában

Abstract

The zeta-chain associated protein of 70 kDa (ZAP-70) was first described by Chan and colleagues in Jurkat cells stimulated through the T cell receptor. Under physiological conditions ZAP-70 is expressed by T cells and NK cells, however in chronic lymphocytic leukemia (CLL) and B cell acute lymphoblastic leukemia (B-ALL) it was found in a subset of B cells, as well. According to latest results, ZAP-70 is expressed in immature and mature B cells under normal conditions as well, however the expression level is significantly lower than that observed in T cells and the lack of ZAP-70 causes no disruption in the development or activation of B cells. ZAP-70 is a member of the Syk (spleen tyrosine kinase) protein kinase family, and it is a key player in the maturation and activation of T cells. Loss-of function mutations or lack of ZAP-70 expression leads to a rare form of severe combined immunodeficiency (SCID) in both humans and mice, as in its absence the development of T cells is arrested in the double positive stage (CD4+CD8+), resulting in virtually no mature T cells in the peripheral lymphoid organs. The maturation and and selection of T cells is a dynamic process taking place in the thymus. The development of T cells starts in the bone marrow, the cells that later colonize the thymus arise from the hematopoietic stem cells (HSC) of the bone marrow. In the pro-T cells phase the main markers of thymocytes are c-kit, CD44 and CD25. Early thymic progenitor cells (ETP) (c-kithi CD44+CD25-) reach DN2a (c-kithi CD44+ CD25+) and later DN2b (c-kitlo CD44+ CD25+) stages. Thymocytes are at that stage CD4- and CD8- double negative (DN), their development is independent of the T cell receptor. The DN thymocytes migrate tot he cortex, where signals originating from cortical epithelial cells (cTEC) promote proliferation and commitment tot he T cell lineage, and paralelly, thymocytes also contribute to the maturation of cTEC precursors into mature cTECs. Rearrangement of T cell receptor (TcR) genes occur in the DN3 (CD4-CD8-CD25+CD44-) stage. This is when the β-selection takes place: if the rearrangement of TcRβ gene is successful, the TcR β protein is expressed ont he surface of the cells, and after combination with the pre-TcR α-chain forms the pre-TcR complex. This is when the decision between αβ or γδ T cell lineage differention occurs. The CD4 and CD8 co-receptor appears on t he surface of thymocytes expressing the αβ TcR. The resulting CD4+ CD8+ double positive (DP) thymocytes start to migrate towards the central part of the thymus, the medulla. The DP thymocytes go through strict selection steps. During the positive selection those DP thymocytes, whose αβ TcR recognizes the own antigen presented on the major histocompatibility complex (MHC) of cTEC recieve survival signals through their TcR and continue their differentiation. As the result of positive selection single positive (SP) thymocytes develop, the thymocytes recognizing MHC I differentiate into CD8 SP, the ones recognizing MHC II differentiate into CD4 SP cells. Those DP thymocytes, whose TcR does not recognize the own peptide-MHC complex does not survive selection and die via apoptosis. The negative selection of autoreactive thymocytes takes place in the medulla, where the medullary epithelial cells (mTEC) play a key role. With the help of the AIRE and Fzf2 transcription factors the mTEC cells express and present a great variety of own tissue antigens through their MHC to the developing thymocytes. To avoid autoimmunity, the thymocytes recognizing own antigens with high affinity are deleted with clonal deletion. However, during the so-called agonist selection some cell populations survive negative selection even though they recognize own antigens, an example is natural regulatory T cells (nTreg). Mature thymocytes that survived selection enter the circulation, where the naive CD4+ T cells become activated and proliferate, and differentiate into various helper T cell (Th) subgroups after encounter with a presented antigen.