Differential immuno-suppressive effects of metabolic inhibitors on T-lymphocyte activation.
An important challenge in the field of auto-immune diseases, bone marrow and organ transplantation is the control of T-lymphocyte activation. To gain more insight into the in vitro correlation of immunosuppression, we investigated the effects of cyclosporin A (CSA) and two other metabolic inhibitors on cytokine secretion and T-cell proliferation. Secretion of TNF-alpha and GM-CSF was much more resistant to metabolic inhibitors than proliferation or synthesis of IL-1 alpha or IL-2. Moreover, our data suggested that the regulation of IL-1 alpha production in T-cells was CSA and protein kinase C (PKC)-dependent, as opposed to monocytes regulation. The receptivity to the epithelial cell-derived cytokine IL-7, associated either with antigen-dependent or independent triggering, was almost similarly inhibited by cyclosporin A, forskolin or PKC inhibitor, in sharp contrast to IL-2 receptivity. In this latter case, CD28+ IL-2 stimulation was more sensitive to both forskolin and PKC inhibition than that of CD2 or CD3+ IL-2. With regard to CSA effects, limiting dilution analysis provided evidence for some heterogeneity at the clonal level. This strongly suggested that T-cell functional monitoring at the population level does not truly reflect the actual immunosuppression. Additional experiments are required to evaluate the sensitivity to metabolic inhibitors of T-lymphocyte activation via the natural ligands of CD2 and CD28.
Costello
R
R
Unité INSERM U119, Marseille, France.
Mawas
C
C
Olive
D
D
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000963:Antimetabolites / Q000494:pharmacology*; D018801:CD2 Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D005576:Colforsin / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000963:Antimetabolites; D018801:CD2 Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D007166:Immunosuppressive Agents; D007211:Indoles; D007376:Interleukin-2; D015851:Interleukin-7; D008301:Maleimides; D011971:Receptors, Immunologic; D005576:Colforsin; D016572:Cyclosporine; D011493:Protein Kinase C; C070515:bisindolylmaleimide I