Opposing effects of TGF-beta and IL-15 cytokines control the number of short-lived effector CD8+ T cells.
An effective immune response against infectious agents involves massive expansion of CD8(+) T cells. Once the infection is cleared, the majority of these effector cells die through unknown mechanisms. How is expansion controlled to maximize pathogen clearance and minimize immunopathology? We found, after Listeria infection, plasma transforming growth factor beta (TGF-beta) titers increased concomitant with the expansion of effector CD8(+) T cells. Blocking TGF-beta signaling did not affect effector function of CD8(+) T cells. However, TGF-beta controlled effector cell number by lowering Bcl-2 amounts and selectively promoting the apoptosis of short-lived effector cells. TGF-beta-mediated apoptosis of this effector subpopulation occurred during clonal expansion and contraction, whereas interleukin-15 (IL-15) promoted their survival only during contraction. We demonstrate that the number of effector CD8(+) T cells is tightly controlled by multiple extrinsic signals throughout effector differentiation; this plasticity should be exploited during vaccine design and immunotherapy against tumors and autoimmune diseases.
Sanjabi
Shomyseh
S
Yale University School of Medicine, New Haven, CT 06520, USA.
Mosaheb
Munir M
MM
Flavell
Richard A
RA
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D008087:Listeria / Q000276:immunology; D008088:Listeriosis / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism
D019409:Interleukin-15; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta