Gammadelta T lymphocyte homeostasis is negatively regulated by beta2-microglobulin.
Successful application of gammadelta 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(+) gammadelta T cell subsets are differentially regulated. While CD8(+) gammadelta T cells have an early and sustained advantage following transfer into TCRbeta(-/-)/delta(-/-) mice, NK1.1(+) gammadelta 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 Vgamma4(+) and Vdelta5(+) expression. Despite the role of CD8 in MHC class I recognition by alphabeta T cells, beta(2)-microglobulin (beta(2)m)-associated MHC class I molecules were not required for CD8(+) gammadelta T cell homeostatic expansion. Surprisingly, all gammadelta T cells, including the CD8(+) subset, exhibited enhanced proliferation following adoptive transfer into Rag1(-/-)/beta(2)m(-/-) 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 beta(2)m, gammadelta T cell homeostatic proliferation in TCRbeta(-/-)/delta(-/-) mice was not altered in the presence of Ly49C/I- and NKG2-blocking Abs. While the mechanism by which beta(2)m negatively regulates gammadelta T cell homeostasis remains to be determined, this observation is unique to gammadelta T cells and confirms that multiple mechanisms are in place to maintain strict regulation of both the size and the composition of the gammadelta T cell pool.
French
Jena D
JD
National Jewish Health, Integrated Department of Immunology, Denver, CO 80206, USA.
Roark
Christina L
CL
Born
Willi K
WK
O'Brien
Rebecca L
RL
D019264:Adoptive Transfer; D000818:Animals; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000276:immunology* / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D016692:Receptors, Antigen, T-Cell, gamma-delta; D018123:Receptors, Interleukin; D001613:beta 2-Microglobulin