On the basis of expression of the T cell differentiation antigen CD27, human peripheral blood CD4+ memory cells can be divided into two subsets, a large CD45RA-CD27+ (82%) and a small CD45RA-CD27- (18%) population. Analysis of the functional properties of these memory T cell subsets showed that proliferative responses to the recall antigen tetanus toxoid (TT), shortly after booster immunization, were mainly confined to the CD27- population. Also, in atopic individuals, proliferative responses to allergens for which these individuals are sensitized, were limited to the CD45RA-CD27- population. After stimulation with CD3 monoclonal antibody and phorbol ester, CD27+ cells produced vast amounts of interleukin (IL)-2 but minimal amounts of IL-4, whereas in marked contrast, CD27- T cells secreted low levels of IL-2 and high levels of IL-4. The capacity of the vast majority of these latter cells to produce IL-4 was found to be a stable feature since high IL-4 secreting T cell clones were generated from the CD27- subset. These findings suggest that upon renewed as well as chronic antigenic stimulation in vivo, memory T cells acquire the CD45RA-CD27- phenotype and that, as a consequence, in this subset functionally differentiated CD4+ T cells are compartmentalized. Our results predict that analysis of the small CD27- subset of memory cells, that makes up approximately 10% of the peripheral blood T cell population, will provide information on the specificity and function of responding CD4+ T cells at a given point in time in healthy and diseased individuals.
We have examined the regulation of interleukin (IL)-4 production by human peripheral blood T cells. Production of IL-4 was shown to be regulated differently from IL-2 and interferon(IFN)-gamma production. Stimulation of peripheral blood lymphocytes with anti-CD3, anti-CD2, anti-CD28, Phorbol 12-myristate 13-acetate (PMA) or IL-2 as a single stimulant did not induce IL-4 production. However, combinations of anti-CD2 with either anti-CD28 or IL-2 resulted in IL-4 production, peaking at days 3-4. Stimulation with anti-CD3 instead of anti-CD2 gave similar results, but was less potent. After days 3-4, IL-4 levels decreased, most likely due to consumption of IL-4. PMA profoundly affected cytokine production, it enhanced IL-2 production by at least tenfold, whereas, in the same cell population, IL-4 production was almost completely inhibited. This was observed at the protein as well as at the mRNA level. In contrast, agents that increase intracellular cAMP levels inhibited IL-2 production but left IL-4 production unaffected. IFN-gamma production behaved similar to IL-2 production but the effects were less outspoken.
To assess the immunological changes occurring during filarial infection with or without elephantiasis, 145 patients in different clinical groups from an endemic area in Indonesia were compared with respect to plasma levels of both soluble CD25 (sCD25) and sCD27; interleukin-4 (IL-4) and interferon-gamma release by peripheral blood mononuclear cells was also measured in a smaller subset of individuals. Levels of sCD27 were significantly elevated in elephantiasis and microfilaremic patients compared with endemic normals (p < 0.002), whereas sCD25 levels remained low in microfilaremics and was only slightly elevated in elephantiasis patients compared with endemic normals (p < 0.02). As activated T cell populations release both sCD27 and sCD25, these findings imply that there is filarial-driven activation of a T cell subset that releases sCD27 rather than sCD25. The expansion of a particular T cell population by filarial parasites is further suggested by the enhancement in both IL-4-producing and CD4+CD27-T cells in PBMC from elephantiasis and microfilaremic patients compared with endemic normals. More detailed characterization and comparison of CD27-lymphocytes from these individuals may identify mechanisms involved in the pathogenesis of lymphatic filariasis.
Regulation of interleukin (IL)-4 production, but not IL-2 production, was found to be quite different in either freshly isolated T cells or T cell clones. Both fresh T cells and T helper 2-like clones produced IL-4 when stimulated with anti-CD2 in combination with anti-CD28. However, whereas T cell clones showed enhanced IL-4 production when phorbol 12-myristate 13-acetate (PMA) was used in addition to anti-CD2 and anti-CD28, IL-4 production by fresh T cells was inhibited by the presence of PMA. Prestimulation of fresh T cells led to the following observations: (a) activation in the absence of PMA led to a reversal of the PMA effect and (b) within 2 days these cells resembled T cell clones in that IL-4 production was no longer inhibited by PMA. When prestimulation was carried out in the presence of PMA, the inhibition of IL-4 production seemed irreversible. Removal of PMA after 3 days did not lead to renewed capability of IL-4 production, whereas IL-2 production was unimpaired. Our data show that the capacity of cultured T cells to produce IL-4 is determined and fixed during the first 2-3 days of stimulation.
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