Functional dichotomy between NKG2D and CD28-mediated co-stimulation in human CD8+ T cells. PLoS One 2010 Sep 09;5(9)
Date
09/17/2010Pubmed ID
20844584Pubmed Central ID
PMC2936560DOI
10.1371/journal.pone.0012635Scopus ID
2-s2.0-77958581426 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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 naïve (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-γ and TNF-α levels. On the contrary, irrespective of its comparable levels, NKG2D-mediated co-stimulation failed to augment IFN-γ and TNF-α production in CD28Hi naïve/memory T cells. Additionally, CD28-mediated co-stimulation was obligatory for IL-2 generation and thereby its production was limited only to the CD28Hi naïve/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 naïve CD8+ T cells would require CD28-mediated co-stimulation.
Author List
Rajasekaran K, Xiong V, Fong L, Gorski J, Malarkannan SAuthor
Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
CD28 AntigensCD8 Antigens
CD8-Positive T-Lymphocytes
Cells, Cultured
Cytokines
Gene Expression
Humans
Lymphocyte Activation
NK Cell Lectin-Like Receptor Subfamily K