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T Lymphocyte Homeostasis Is Negatively Regulated by β2-Microglobulin1National Jewish Health, Integrated Department of Immunology, Denver, CO 80206
Successful application of 
T cells in adoptive cell therapies depends upon our ability to maintain these cells in vivo. Using an adoptive transfer model to study lymphopenia-induced homeostatic expansion, we show that CD8+ and NK1.1+ T cell subsets are differentially regulated. While CD8+ T cells have an early and sustained advantage following transfer into TCRβ–/–/–/– mice, NK1.1+ T cells proliferate slowly and are maintained at low numbers. The advantage of the CD8+ subset could not be explained by increased bcl-2 or cytokine receptor expression but did correlate with V4+ and V5+ expression. Despite the role of CD8 in MHC class I recognition by 
β T cells, β2-microglobulin (β2m)-associated MHC class I molecules were not required for CD8+ T cell homeostatic expansion. Surprisingly, all T cells, including the CD8+ subset, exhibited enhanced proliferation following adoptive transfer into Rag1–/–/β2m–/– compared with Rag1–/– recipients. This effect was most notable for the NK1.1+ subset, which expresses high levels of NKG2A/CD94 and Ly49. Although expression of these inhibitory receptors correlated with poor homeostatic expansion in the presence of β2m, T cell homeostatic proliferation in TCRβ–/–/–/– mice was not altered in the presence of Ly49C/I- and NKG2-blocking Abs. While the mechanism by which β2m negatively regulates T cell homeostasis remains to be determined, this observation is unique to T cells and confirms that multiple mechanisms are in place to maintain strict regulation of both the size and the composition of the T cell pool.
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 supported by National Institutes of Health Grant 2R01A144920 (to R.L.O.).
2 Current address: University of Colorado, Anschutz Medical Campus, Endocrinology Division, School of Medicine, Denver, CO 80010.
3 Current address: Beacon Biotechnology, Aurora, CO 80045.
4 Address correspondence and reprint requests to Dr. Rebecca L. O'Brien, National Jewish Health, Integrated Department of Immunology, Denver, CO 80206. E-mail address: obrienr{at}njhealth.org
5 Abbreviations used in this paper: MHC I, MHC class I; β2m, β2-microglobulin.
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