Heterogeneity in Lymphokine Profiles of CD4⁺ and CD8⁺ T Cells and Clones Activated in vivo and in vitro

Abstract

Analysis of lymphokine mRNA expression and protein secretion by about 100 short-term alloreactive T-cell clones revealed marked heterogeneity in the combinations of lymphokines synthesized. This finding argues against a simple model in which T cells express either an unrestricted (Th0) or a restricted (Th1 or Th2) lymphokine profile. Lymphokine titers appeared to be normally distributed, with the percentage of positive clones for any one product determined by the threshold of detection. Accordingly, the observation that CD4+ clones on average produced higher titers of most lymphokines than CD8+ clones indicated that apparent differences between the lymphokine profiles of these two subsets were quantitative rather than qualitative. Patterns of lymphokine gene expression detected in whole tissues or by analysis of single cells and clones were markedly influenced by in vivo priming. Relative levels of expression of IL-4, IFN-gamma and GM-CSF in lymphoid tissues differed in mice undergoing a GvHR or following contact sensitization with OX or immunization with KLH in adjuvant. Consistent with the finding that IL-4 was the major lymphokine mRNA detected in lymph nodes of KLH-primed mice, most short-term KLH-specific clones derived from such mice also expressed IL-4. A similar approach to the detection of lymphokine-secreting T-cell precursors activated late in L. major infection showed that most clones from the L. major-resistant strain, C57BL/6, secreted IFN-gamma without IL-4 whereas most clones from the susceptible strain, BALB/c, secreted IL-4 without IFN-gamma. Differences were also noted in anti-CD3-induced IL-3 production at the single-cell level between CD8+ cells activated in the GvHR or against a tumor allograft. Con A-induced, filler cell-dependent cloning of CD4+ T cells from unprimed mice gave rise both to IFN-gamma-producing and to IL-4-producing clones. A requirement for an undefined, filler cell-dependent signal for development of IL-4-secreting clones was suggested by the finding that clones of normal CD4+ and CD8+ T cells activated in an anti-CD3-induced, filler cell-free system exclusively produced IFN-gamma and IL-3 without detectable IL-4 or IL-6. With a view to developing a single-cell approach to the analysis of lymphokine profiles of in vivo-activated T cells, sensitive assays for IL-3 and other lymphokines were used to measure secreting cells activated in the GvHR or against a tumor allograft.(ABSTRACT TRUNCATED AT 400 WORDS)

Normal hematopoiesis is maintained by activated bone marrow CD4+ T cells

“…Activated T cells produce IL-6, but G-CSF production was never reported. 6 However, we believe that T cells could be stimulating production of G-CSF by other cell types in the BM microenvironment. In fact, OSM has been shown to stimulate endothelial G-CSF expression and, consequently, granulopoiesis.…”

“…4,5 During adaptive immune responses, T cells can produce a diverse set of cytokines related to hematopoiesis regulation, such as interleukins 3, 4, 5, 6, 13, 17, and granulocyte-macrophage colony-stimulating factor (GM-CSF). [6][7][8][9][10][11][12] Some of these hematopoietins are known to up-regulate host innate immune response to control pathogen dissemination during bacterial and helminthic infections. [13][14][15] More recently, the pleomorphic T helper 1 (Th1)-derived cytokine oncostatin M (OSM) was suggested as a regulator of normal hematopoietic homeostasis.…”

Abnormal T Cell Receptor Signal Transduction of CD4 Th Cells in X-Linked Lymphoproliferative Syndrome

“…A MLR induces drastic activation of target cells, which induces a significant level of cytokine production (66,67). To further examine T cell responsiveness, we examined the MLR response of HVS-transformed control CD4 T cells and HVS-transformed XLP CD4 T cells with autologous or heterologous B lymphocytes by measuring IL-2 and IFN-␥ cytokine production.…”

Cytokine gene polymorphism in human disease: on-line databases

“…Both TH1 and TH2 cells produce IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF). [13][14][15][16][17][18][19][20] Recently a TH3 subset (characterized by TGF␤) has been defined. In humans, the distinction between TH1, TH2 and TH3 is less well defined, and a subset of TH0 cells, which produce some cytokines typical of TH1 and TH2 profiles can be identified.…”