Induction of Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) Restricts Clonal Expansion of Helper T Cells

doi:10.1084/jem.194.7.893

Published online 1 October 2001. doi:10.1084/jem.194.7.893

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© The Rockefeller University Press, 0022-1007/2001/10/893/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 7, October 1, 2001 893-902

Original Article

Induction of Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) Restricts Clonal Expansion of Helper T Cells

Alden M. Doyle^a, Alan C. Mullen^a, Alejandro V. Villarino^a, Anne S. Hutchins^a, Frances A. High^a, Hubert W. Lee^a, Craig B. Thompson^a, and Steven L. Reiner^a

^a Abramson Family Cancer Research Institute, and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
University of Pennsylvania, 421 Curie Blvd., Rm. 414 Philadelphia, PA 19104-6160.215-746-5525215-746-5536

sreiner{at}mail.med.upenn.edu

Cytotoxic T lymphocyte antigen (CTLA)-4 plays an essential rolein immunologic homeostasis. How this negative regulator of Tcell activation executes its functions has remained controversial.We now provide evidence that CTLA-4 mediates a cell-intrinsiccounterbalance to restrict the clonal expansion of proliferatingCD4⁺ T cells. The regulation of CTLA-4 expression and functionensures that, after $~$ 3 cell divisions of expansion, most progenywill succumb to either proliferative arrest or death over theensuing three cell divisions. The quantitative precision ofthe counterbalance hinges on the graded, time-independent inductionof CTLA-4 expression during the first three cell divisions.In contrast to the limits imposed on unpolarized cells, T helpertype 1 (Th1) and Th2 effector progeny may be rescued from proliferativearrest by interleukin (IL)-12 and IL-4 signaling, respectively,allowing appropriately stimulated progeny to proceed to thestage of tissue homing. These results suggest that the cell-autonomousregulation of CTLA-4 induction may be a central checkpoint ofclonal expansion of CD4⁺ T cells, allowing temporally and spatiallyrestricted growth of progeny to be dictated by the nature ofthe threat posed to the host.

Key Words: lymphocyte • CTLA-4 • cell cycle • CD4⁺ • CCR7

Abbreviations used in this paper: CCR, CC chemokine receptor;CFSE, carboxy-fluorescein diacetate succinimidyl ester; CTLA,cytotoxic T lymphocyte antigen; HPRT, hypoxanthine guanine phosphoribosyltransferase; RT, reverse transcription.

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