γδ T Lymphocyte Homeostasis Is Negatively Regulated by β2-Microglobulin

Abstract

Successful application of γδ 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+ γδ T cell subsets are differentially regulated. While CD8+ γδ T cells have an early and sustained advantage following transfer into TCRβ−/−/δ−/− mice, NK1.1+ γδ 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 Vγ4+ and Vδ5+ expression. Despite the role of CD8 in MHC class I recognition by αβ T cells, β2-microglobulin (β2m)-associated MHC class I molecules were not required for CD8+ γδ T cell homeostatic expansion. Surprisingly, all γδ 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, γδ T cell homeostatic proliferation in TCRβ−/−/δ−/− mice was not altered in the presence of Ly49C/I- and NKG2-blocking Abs. While the mechanism by which β2m negatively regulates γδ T cell homeostasis remains to be determined, this observation is unique to γδ T cells and confirms that multiple mechanisms are in place to maintain strict regulation of both the size and the composition of the γδ T cell pool.