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Published online on July 3, 2007, 10.1073/pnas.0705007104
PNAS | July 10, 2007 | vol. 104 | no. 28 | 11730-11735


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BIOLOGICAL SCIENCES / IMMUNOLOGY
Expression of IL-7 receptor {alpha} is necessary but not sufficient for the formation of memory CD8 T cells during viral infection

Timothy W. Hand*, Michel Morre{dagger}, and Susan M. Kaech*,{ddagger}

*Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and {dagger}Cytheris, Inc., 92130 Issy-les-Moulineaux, France

Communicated by Richard A. Flavell, Yale University School of Medicine, New Haven, CT, May 29, 2007 (received for review February 13, 2007)

During many acute viral and bacterial infections, IL-7 receptor {alpha}-chain (IL-7R{alpha}) is expressed on a subset of effector CD8 T cells that preferentially develop into long-lived memory CD8 T cells. These cells functionally require IL-7R{alpha}, but it is unclear whether IL-7R{alpha} acts mainly to induce their differentiation into memory cells or to sustain their long-term survival. To examine this question, IL-7R{alpha} was constitutively overexpressed on all antigen-specific effector CD8 T cells during viral infection. Constitutive IL-7R{alpha} expression had minimal effects on the numbers or function of effector and memory CD8 T cells formed. This indicated that IL-7R{alpha} expression is not sufficient to drive memory cell development. In particular, the forced IL-7R{alpha} expression did not rescue the killer cell lectin-like receptor G1 (KLRG1)hi short-lived effector CD8 T cells from death, showing that the majority of effector CD8 T cells die in an IL-7R{alpha}-independent manner. Moreover, we found that, regardless of the ectopic expression of IL-7R{alpha}, the KLRG1hi, but not the KLRG1lo effector CD8 T cells, were unable to proliferate well to IL-7, which may be due to increased amounts of p27kip in KLRG1hi cells. Because IL-7 can destabilize p27kip, this result suggested that KLRG1hi and KLRG1lo effector CD8 T cells naturally differ in their ability to transmit IL-7 signals. Altogether, these results reveal that IL-7R{alpha} expression is permissive, but not instructive, to the creation of memory CD8 T cells.

p27kip | T cell homeostasis | T cell memory

Author contributions: T.W.H. and S.M.K. designed research; T.W.H. performed research; M.M. contributed new reagents/analytic tools; T.W.H. and S.M.K. analyzed data; and T.W.H. and S.M.K. wrote the paper.

Conflict of interest statement: M.M. is the Chief Executive Officer of Cytheris. Cytheris's product, recombinant human IL-7, was used in the production of this work.

This article contains supporting information online at www.pnas.org/cgi/content/full/0705007104/DC1.

{ddagger}To whom correspondence should be addressed. E-mail: susan.kaech{at}yale.edu

© 2007 by The National Academy of Sciences of the USA


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