Regulation of murine lymphokine production in vivo. III. The lymphoid tissue microenvironment exerts regulatory influences over T helper cell function.

We investigated the capacity of murine T lymphocytes, isolated from various lymphoid organs of normal or antigen-primed donors, to produce IL-2 or IL-4 after activation with anti-CD3 or specific antigen. Our results established that T cells resident within lymphoid organs being drained by nonmucosal tissue sites (e.g., axillary, inguinal, brachial lymph nodes, or spleen) produced IL-2 as the predominant T cell growth factor (TCGF) after activation. Conversely, activated T cells from lymphoid organs being drained by mucosal tissues (Peyer's patches, and cervical, periaortic, and parathymic lymph nodes) produced IL-4 as the major species of TCGF. Analysis of the lymphoid tissues obtained from adoptive recipients of antigen-primed lymphocytes provided by syngeneic donors provided evidence that direct influences were being exerted on T cells during their residence within defined lymphoid compartments. These lymphoid tissue influences appeared to be responsible for altering the potential of resident T cells to produce distinct species of TCGF. Steroid hormones, known transcriptional enhancers and repressors of specific cellular genes, were implicated in the controlling mechanisms over TCGF production. Glucocorticoids (GCs) were found to exert a systemic effect on all recirculating T cells, evidenced by a marked dominance in IL-4 production by T cells obtained from all lymphoid organs of GC-treated mice, or after a direct exposure of normal lymphoid cells to GCs in vitro before cellular activation with T cell mitogens. Further, the androgen steroid DHEA appeared to be responsible for providing an epigenetic influence to T cells trafficking through peripheral lymphoid organs. This steroid influence resulted in an enhanced potential for IL-2 secretion after activation. Anatomic compartmentalization of the DHEA-facilitated influence appears to be mediated by differential levels of DHEA-sulfatase in lymphoid tissues. DHEA-sulfatase is an enzyme capable of converting DHEA-sulfate (inactive) to the active hormone DHEA. We find very high activities of this enzyme isolated in murine macrophages. The implications of our findings to immunobiology are very great, and indicate that T cells, while clonally restricted for antigen peptide recognition, also appear to exhibit an extreme flexibility with regards to the species of lymphokines they produce after activation. Regulation of this highly conservative mechanism appears to be partially, if not exclusively, controlled by cellular influences being exerted by distinct species of steroid hormones, supplied in an endocrine or a paracrine manner where they mediate either systemic or tissue-localized influences, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)