Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 20, Pages 9311-9316Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0913729107
Keywords
cytotoxic T lymphocyte; homeostasis; cytokine
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Funding
- Center for Human Immunology
- Canadian Institutes of Health Research
- Canadian Allergy, Asthma and Immunology Foundation
- Fonds de la Recherche en Sante du Quebec
- Canadian Louis Pasteur Foundation
- Institut Pasteur
- Institut National de la Sante et de la Recherche Medicale
- European Community Network of Excellence [MUGEN LSHG-CT-2005-005203]
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Several cytokines (including IL-2, IL-7, IL-15, and IL-21) that signal through receptors sharing the common gamma chain (gamma(c)) are critical for the generation and peripheral homeostasis of naive and memory T cells. Recently, we demonstrated that effector functions fail to develop in CD4(+)T cells that differentiate in the absence of gamma(c). To assess the role of gamma(c) cytokines in cell-fate decisions that condition effector versus memory CD8(+)T cell generation, we compared the response of CD8(+)T cells from gamma(c) + or gamma(-)(c) P14 TCR transgenic mice after challenge with lymphocytic choriomeningitis virus. The intrinsic IL-7-dependent survival defect of gamma(-)(c) naive CD8+T cells was corrected by transgenic expression of human Bcl-2. We demonstrated that although gamma(c)-dependent signals are dispensable for the initial expansion and the acquisition of cytotoxic functions following antigenic stimulation, they condition the terminal proliferation and differentiation of CD8(+) effector T cells (i.e., KLRG1(high) CD127(low) short-lived effector T cells) via the transcription factor, T-bet. Moreover, the gamma(c)-dependent signals that are critical for memory T cell formation are not rescued by Bd2 overexpression. Together, these data reveal an unexpected divergence in the requirement for gamma(c) cytokines in the differentiation of CD4(+) versus CD8(+) cytotoxic T lymphocytes.
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