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CD127 and CD25 Expression Defines CD4⁺ T Cell Subsets That Are Differentially Depleted during HIV Infection ¹

Richard M. Dunham^*,, Barbara Cervasi^*, Jason M. Brenchley, Helmut Albrecht, Amy Weintrob, Beth Sumpter, Jessica Engram^*, Shari Gordon^*,, Nichole R. Klatt^*,, Ian Frank^*, Donald L. Sodora^¶, Daniel C. Douek, Mirko Paiardini^* and Guido Silvestri^2,*,

^* Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Emory Vaccine Center, Emory University School of Medicine, and Yerkes National Primate Research Center, Atlanta, GA 30322; Human Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Infectious Diseases Clinic, Crawford-Long Hospital, Atlanta, GA 30308; and ^¶ Seattle Biomedical Research Institute, Seattle, WA 98109

Decreased CD4⁺ T cell counts are the best marker of disease progression during HIV infection. However, CD4⁺ T cells are heterogeneous in phenotype and function, and it is unknown how preferential depletion of specific CD4⁺ T cell subsets influences disease severity. CD4⁺ T cells can be classified into three subsets by the expression of receptors for two T cell-tropic cytokines, IL-2 (CD25) and IL-7 (CD127). The CD127⁺CD25^low/– subset includes IL-2-producing naive and central memory T cells; the CD127^–CD25^– subset includes mainly effector T cells expressing perforin and IFN-; and the CD127^lowCD25^high subset includes FoxP3-expressing regulatory T cells. Herein we investigated how the proportions of these T cell subsets are changed during HIV infection. When compared with healthy controls, HIV-infected patients show a relative increase in CD4⁺CD127^–CD25^– T cells that is related to an absolute decline of CD4⁺CD127⁺CD25^low/– T cells. Interestingly, this expansion of CD4⁺CD127^– T cells was not observed in naturally SIV-infected sooty mangabeys. The relative expansion of CD4⁺CD127^–CD25^– T cells correlated directly with the levels of total CD4⁺ T cell depletion and immune activation. CD4⁺CD127^–CD25^– T cells were not selectively resistant to HIV infection as levels of cell-associated virus were similar in all non-naive CD4⁺ T cell subsets. These data indicate that, during HIV infection, specific changes in the fraction of CD4⁺ T cells expressing CD25 and/or CD127 are associated with disease progression. Further studies will determine whether monitoring the three subsets of CD4⁺ T cells defined based on the expression of CD25 and CD127 should be used in the clinical management of HIV-infected individuals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by Grants R01 AI52755 and R01 AI66998 from the National Institute of Allergy and Infectious Diseases (to G.S.) and from Grant RR-00165 from the National Center for Research Resources (to the Yerkes National Primate Research Center).

² Address correspondence and reprint requests to Dr. Guido Silvestri, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 705 Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104. E-mail address: gsilvest{at}mail.med.upenn.edu

³ Abbreviations used in this paper: T_N, naive T; T_M, memory T; T_E, effector T; Treg, regulatory T cell; SM, sooty mangabey.