TCR signaling inhibits glucocorticoid-induced apoptosis in murine thymocytes depending on the stage of development.
Signaling by either the TCR or glucocorticoid receptor (GR) induces apoptosis in thymocytes. Interestingly, it has been shown previously that hybridoma T cells escape apoptosis induced by either TCR or GR when both of these receptors signal simultaneously. Whether such mutual antagonism is present in primary thymocytes was the subject of the present study. Both glucocorticoids (GC) and anti-TCR/CD28 (or anti-CD3/CD28) mAb induced apoptosis in total thymocytes. When these signals were present at the same time, GC-induced apoptosis was partially inhibited by TCR/CD3 signaling. Costimulation by anti-CD28 enhanced the inhibitory effects of anti-CD3 on GC-induced apoptosis about 30-fold. However, subset analysis revealed that most cells rescued from GC-induced apoptosis were mature CD4+ and CD8+ thymocytes, and these cells were resistant to TCR/CD3-induced apoptosis in the absence of GC. Similar results were obtained with mature splenic CD4+ and CD8+ T cells. TCR/CD3 signaling alone, while inducing apoptosis in CD4+(CD8+)TCRlow thymocytes, rescued a small subset of CD4+(CD8+)TCRlow thymocytes from GC-induced apoptosis. Thus, TCR signaling increasingly reverses GC-induced apoptosis as thymocyte development progresses. As GC are infinitely present in vivo, these findings support a model wherein TCR signaling may be required to prevent GC-induced apoptosis both under basal and immune challenging conditions.
Erlacher
Miriam
M
Division of Experimental Pathophysiology and Immunology, Biocenter, Innsbruck Medical University, Austria.
Knoflach
Michael
M
Stec
Ilona E M
IE
Böck
Günther
G
Wick
Georg
G
Wiegers
G Jan
GJ
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006727:Hormone Antagonists / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*
D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D005938:Glucocorticoids; D006727:Hormone Antagonists; D011948:Receptors, Antigen, T-Cell; D011965:Receptors, Glucocorticoid; D015735:Mifepristone