%0 Journal Article
%T Functional Dichotomy between NKG2D and CD28-Mediated Co-Stimulation in Human CD8+ T Cells
%A Kamalakannan Rajasekaran
%A Va Xiong
%A Lee Fong
%A Jack Gorski
%A Subramaniam Malarkannan
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0012635
%X Both CD28 and NKG2D can function as co-stimulatory receptors in human CD8+ T cells. However, their independent functional contributions in distinct CD8+ T cell subsets are not well understood. In this study, CD8+ T cells in human peripheral blood- and lung-derived lymphocytes were analyzed for CD28 and NKG2D expression and function. We found a higher level of CD28 expression in PBMC-derived na£¿ve (CD45RA+CD27+) and memory (CD45RA£¿CD27+) CD8+ T cells (CD28Hi), while its expression was significantly lower in effector (CD45RA+CD27£¿) CD8+ T cells (CD28Lo). Irrespective of the differences in the CD28 levels, NKG2D expression was comparable in all three CD8+ T cell subsets. CD28 and NKG2D expressions followed similar patterns in human lung-resident GILGFVFTL/HLA-A2-pentamer positive CD8+ T cells. Co-stimulation of CD28Lo effector T cells via NKG2D significantly increased IFN-¦Ã and TNF-¦Á levels. On the contrary, irrespective of its comparable levels, NKG2D-mediated co-stimulation failed to augment IFN-¦Ã and TNF-¦Á production in CD28Hi na£¿ve/memory T cells. Additionally, CD28-mediated co-stimulation was obligatory for IL-2 generation and thereby its production was limited only to the CD28Hi na£¿ve/memory subsets. MICA, a ligand for NKG2D was abundantly expressed in the tracheal epithelial cells, validating the use of NKG2D as the major co-stimulatory receptor by tissue-resident CD8+ effector T cells. Based on these findings, we conclude that NKG2D may provide an expanded level of co-stimulation to tissue-residing effector CD8+ T cells. Thus, incorporation of co-stimulation via NKG2D in addition to CD28 is essential to activate tumor or tissue-infiltrating effector CD8+ T cells. However, boosting a recall immune response via memory CD8+ T cells or vaccination to stimulate na£¿ve CD8+ T cells would require CD28-mediated co-stimulation.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012635