T-cell maturation

Campbell JJ, Pan J, Butcher EC. Cutting edge developmental switches in chemokine responses during T cell maturation. J Immunol 1999 163(5) 2353-2357. 

Thymosin is an immunomodulatory peptide produced by the thymus gland and other cells. Thymosin alfa 1, a 28-amino acid peptide, is one member of the family of thymosins that collectively appear to influence a variety of regulatory and counter-regulatory functions in terms of T-cell maturation and antigen recognition, stimulation of native interferons and cytokines such as interleukin-2, and activity of natural killer cell-mediated cytotoxicity. In some countries it is approved as an adjuvant for influenza vaccine or as a treatment for chronic hepatitis B and, in combination with interferon for hepatitis C. Thymosin alfa 1 has been used with some success to treat children with the severe form of Di-George Syndrome. 

Interleukin-21 (IL-21) Promotes proliferation of activated T cells, maturation of NK cells... 

Jenkmson, E, J., Anderson, G, and Owen, J J T (1992) Studies on T cell maturation on defined thymic stromal cell populations in vitro. J Exp. Med 176,845-853... 

Experimental studies in laboratory rodents have demonstrated that a diverse array of chemical exposures suppress immune function (Table 19.2). In addition a limited number of clinical and epidemiologic studies have reported suppression of immune function and/or increased frequency of infectious and/or neoplastic disease following exposure of humans to some of these agents. From the description above it is clear there are a number of cellular and molecular targets for chemicals that act as immunosuppressants. Clearly, a chemical that disrupts cell proliferation would affect clonal expansion. Disruption of T cell maturation in the thymus is another potential mechanism for immune suppression. Chemicals may also interfere with receptor ligand binding at the cell... 

Dibenzodioxins, including TCDD (dioxin), have been demonstrated to cause severe thymic atrophy with resulting effects on the immune system. The target seems to be the epithelial cells in the thymus, and it is interesting that thymus cells contain the TCDD receptor. Thymic atrophy correlates with the presence of this receptor, and other compounds which compete with TCDD for this receptor also cause thymic atrophy. The basis of the toxicity of TCDD to the thymus may be an effect on T-cell maturation and differentiation. The result of exposure of animals to TCDD is depressed antibody responses, increased susceptibility to infectious agents, and depressed T-cell function. In humans exposed to TCDD occupationally, decreased serum levels of some immunoglobulins and depressed lymphocyte responses to mitogens were reported. 

The concept that thymic hormones exist is now well accepted. However, many controversies still persist because of the multiplicity of different thymic products that have been isolated from thymus tissue over the past several decades. Many of the peptides appear to fulfill at least some of the accepted criteria for categorization as true thymic hormones. However, it is still unclear whether the various thymic polypeptides are components of a single thymic hormone (prohormone) that is capable of exhibiting the complete gamut of biologic properties ascribed to all of the different thymic peptides or whether each peptide alone or in certain combinations with other factors, at both intrathymic and extrathymic locations, regulates specific steps of T cell maturation. In this section we will review the biologic properties attributable to thymic factors in both animals and man. 

Thus, the bulk of evidence available to date would suggest at least in mice that the spleen contains a population of thymic hormone-responsive lymphoid cells that functions mainly in the suppression of immune responses, perhaps masking concomitant helper effects. In the thymus, the predominant effects of thymic peptides appear to be the induction of functional helper cells, possibly by the enhancement of lymphokine production. The effects of thymulin, thymosin, or other thymic factors on IL-2 production may indeed represent a major function of the endocrine thymus, since IL-2 has been shown to be a potent physiological promoter of T cell maturation (Ruscetti and Gallo, 1981). 

Campbell, J. J., Pan, J., and Butcher, E. C. (1999). Cutting edge Developmental switches in ehemokine responses during T-cell maturation. J. Immunol 163, 2353-2357. 

Biotin deficiency in mice changes the subpopnlations of spleen lymphocytes and decreases the proliferative response of spleenocytes to concanavalin A (17). They have also shown that in experimental biotin deficiency the involution of the thymus is accelerated and thymocyte maturation is arrested in the double negative (DN-4) substage. A specific stage in the T cell maturation process is thus sensitive to biotin deficiency (18). 

The T cell defect in children with congenital thymic aplasia varies from the most profound to the barely discernible In any case, T cell function improves in these children with age, so that by five years of age no T cell deficit can be ascertained. It is not clear how this grossly retarded T cell maturation... 

The cause of the T-cell depletion in peripheral blood is not certain. In preliminary unpublished studies Chandra and we (Keusch, Urrutia, Goldstein) have found that thymic hormones will induce the sheep erythrocyte rosette marker in vitro in PEM children with severely depressed T-cell numbers. There is also a suggestion of decreases in the level of circulating thymic hormone. However, the relevance of these findings to the process of T-cell maturation in PEM is uncertain, since the critical events undoubtedly take place within the thymic micro-environment itself and not in the periphery. However, Beatty and Dowdle (1978) have recently demonstrated that mitogenic responses of normal peripheral lymphocytes are suppressed in serum from Kwashiorkor patients compared to normal AB serum.. 

In spite of many early investigations with specific nutrient or vitamin deficiencies and protein deprivation in animals showing very significant decreases in antibody responses to a number of test antigens (Scrimshaw et al, 1968), it is not at all well established that major abnormalities occur in the human with PEM. To the extent that specific antibody responses are T-lymphocyte dependent, then altered T-cell maturation will impact upon B-cell function and diminished antibody may result, even though the B-cell system is itself functioning perfectly well,... 

---