Thymic and extrathymic lymphocyteMaturation
- Crossroads ofextrathymic lymphocytesmaturation pathways

Intrathymic lymphocyte maturation includes several closely related processes: migration, proliferation, differentiation and selection of thymocytes. The developing T cells within the thymus initially populate the outer cortex, where they undergo population growth, rearrangement of TCR genes and surface expression of CD3, TCR, CD4 and CD8 molecules. As thymic lymphocytes mature, they migrate from cortex to medulla. During this migration, lymphocytes go through three main developmental stages defined based on CD4 and CD8 expression.

In the earliest maturation stage, the cortical thymocytes are TCRαβ+ or TCRγδ+CD4-CD8- double negative (DN) cells. Afterward, they became TCRαβ+CD4+CD8+ double positive (DP) cells. TCRγδ+ lymphocytes are DN in stages of full maturity, while TCRαβ+ lymphocytes are DN only in earliest stages of intrathymic development. Finally, mature medullar thymocytes are TCRαβ+CD4+CD8- or TCRαβ+CD4-CD8+ single positive (SG) cells. Adult thymus contains about 5% DN, 80% DP 12% TCRαβ+CD4+CD8-and 3% TCRαβ+CD4-CD8+ SG lymphocytes. During these intrathymic transformations lymphocytes pass through positive and negative selection. Self-reactive thymocytes die by apoptotic mechanism, but remainder self-tolerant thymocytes become mature lymphocytes and soon leave the thymus (1–3).

The thymus is the major site of maturation of both helper T (Th) and cytotoxic cells (CTLs). If the thymus is removed from a neonatal mouse, this animal does not develop a normal T cell repertoire and remains in T cells throughout its life. The congenital absence of the thymus in humans (Di George syndrome) or in the ‘‘nude’’ mouse strain is characterized by low mature T cells in peripheral lymphoid organs and circulation, and deficiencies in T cell mediated immunity (4,5). However, the fact that some phenotypic mature and functional T cells do exist in athymic individuals or animals suggests conclusion that extrathymic sites of T cell maturation may exist. It may be that the remnant of the involuted thymus is adequate for some T cell maturation or that other tissues can assume the role of the thymus. Today we know that some T cells called extrathymic T cells have been found to become mature lymphocytes in extrathymic conditions without support by the thymus.

Tamauchi et al. (6) have demonstrated that TCRαβ+ DP thymocytes injected in athymic mice can develop into TCRαβ+CD4+CD8- and TCRαβ+CD4-CD8+ SG cells in extrathymic tissues. Same authors have experimental results that liver cells can influence lymphocyte maturation in athymic nude mice (6). Moreover, RAG1, RAG2 and pre-T cell receptor a chain expression as markers of lymphocyte immaturity are discovered in adult human hepatic T cells (7). These results suggest that pre-T cells are trafficking from the bone marrow or the thymus to other tissues to continue differentiation and selection in the context of an appropriate cellular and molecular environment. The presence of immature populations of T cells in the adult liver and high levels of RAG expression suggests that the adult liver provides such an environment for extrathymic T cell maturation. Except liver, there are many evidences that extrathymic lymphocytes maturation (eTLM) is possible in other tissues like epithelial tissue and peripheral lymphoid organs, for example Peyer’s patches (8–10).

Thymic epithelial cells, dendritic cells and macrophages play an important role in processes of thymic maturation, including positive and negative selection. At the same time, there are data that similar cells are included in extrathymic lymphocyte selection (6,9,11). Kadena et al. (12) have found that the TCRαβ+ DN T cells develop through a unique extrathymic pathway through bacterial induced activation and accumulation of peritoneal macrophages (12). Signal for activation of eTLM probably is TNF-β, while same signal can be inhibitor of thymic maturation pathway (12,13). Moreover, there are data that eTLM process includes selection of self-reactive clones. Extrathymic selection process probably may go according to apoptotic death of self-reactive clones, but proliferation and full maturity of the clones is also possible. In vitro studies have demonstrated antigen-specific induction of apoptosis in TCRαβ+ DP thymocytes cultured in suspension, by thymic as well as splenic APCs. Thus, the recognition of antigen by TCRαβ+ DP thymocytes may lead to clonal deletion, which is not limited by the antigen-presenting ability of the thymic stroma (14). Because population of immature extrathymic T cells comprise both TCRαβ+ cells and TCRγδ+ cells in different maturation stages, some authors have evidences about phenomenon of TCR gene rearrangement in extrathymic lymphocytes (15–18). Sites of eTLM contain DN self-reactive oligoclones and constitutively express the IL-2 receptor b-chain (15). Borenstein et al. (19) showed that neonatal MHC class I tolerance in the adult is associated with low-level hematopoietic chimerism and extrathymic deletion of alloreactive SG CD8+ T cells. These data indicate that the process of (self)reactive clones negative selection or (self)antigen-reactive clones production like extrathymic phenomenon is possible (19).

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