Cytokines in the thymus: production and biological effects.

All types of thymic cells are able to produce cytokines either spontaneously or after stimulation. The main producers of cytokines in the thymus are thymic epithelial cells (TEC) and thymocytes. Thymic cytokines act at short distance and their effects are limited by the internal space of the organ. The spectrum of biological effects of thymic cytokines is determined by the expression of cytokine receptors on the thymic cell surface. Some cytokines produced by the thymic cells of one type are supplied to cells of other types; other cytokines act as autocrine factors. Examples of paracrine thymic cytokines are IL-7 (produced by TEC or stromal fibroblasts induces CD4(-)CD8(-) thymocyte growth and differentiation) and INFgamma (produced by thymocytes, induces TEC activation). An example of an autocrine factor is IL-2, for which the producers and targets are thymocytes. The ability of thymocytes to produce cytokines and express cytokine receptors is gradually reduced as they mature from the stage of CD44(+)CD3(-)CD4(-)CD8(-) precursor cells to the stage of CD3(lo)CD4(+)CD8(+) cortical thymocytes; in the latter stage both these capacities become completely blocked. This change reflects the decrease of cytokine dependence of the respective processes. After the completion of the selection process, the capacity of thymocytes to produce cytokines and respond to their action is restored. Some differences in the function of the cytokine system in thymus and peripheral compartments of the immune system can be noted. 1. Unlike the periphery, where cytokine production and receptor expression are inducible, the synthesis of cytokines and expression of their receptors in the thymus has mainly a "spontaneous" character (or it is induced by cell-cell interactions). 2. Cytokines tightly interact, forming a cytokine network both at the periphery and in the thymus, but the structure of the peripheral and intrathymic cytokine network is different. The latter can be termed as a "minor cytokine network". Some peptide hormone-like factors play a significant role in the intrathymic cytokine network. 3. The principal role of thymic cytokines is to provide constitutive processes (migration and development of thymocytes, regulation of cell number in the cell populations, etc.), but not inducible ones (inflammation, immune response, etc.) as in the periphery. 4. The functions of some cytokines in the thymus can be significantly different from those in the periphery of the immune system. For example, proinflammatory cytokines act in the thymus as factors or cofactors of thymocyte or TEC activation, proliferation or differentiation. The key cytokines of Th1 and Th2 cells - IFNgamma and IL-4 - do not participate in the immune response but mediate the dialogue between thymocyte and TEC and play a role in autoregulating the thymocyte population. The functions of many cytokines in the thymus are not established up to now. Detailed analysis of the "minor cytokine network" and intrathymic cytokine effects will reveal some unknown events of thymus physiology.