Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus

The human NKG2D killer lectin-like receptor (KLR) is coupled by the DAP10 adapter to phosphoinositide 3-kinase (P13 K) and specifically interacts with different stress-inducible molecules (i.e. MICA, MICB, ULBP) displayed by some tumour and virus-infected cells. This KLR is commonly expressed by human NK cells as wen as TCRγδ ⁺ and TCRαβ⁺CD8⁺ T lymphocytes, but it has been also detected in CD4⁺ T cells from rheumatoid arthritis and cancer patients. In the present study, we analysed NKG2D expression in human cytomegalovirus (HCMV)-specific CD4⁺ T lymphocytes. In vitro stimulation of peripheral blood mononuclear cells (PBMC) from healthy seropositive individuals with HCMV promoted variable expansion of CD4⁺NKG2D⁺ T lymphocytes that coexpressed perforin. NKG2D was detected in CD28^- and CD28^dull subsets and was not systematically associated with the expression of other NK cell receptors (i.e. KIR, CD94/NKG2 and ILT2). Engagement of NKG2D with specific mAb synergized with TCR-dependent activation of CD4⁺ T cells, triggering proliferation and cytokine production (i.e. IFN-γ and TNF-α). Altogether, the data support the notion that NKG2D functions as a prototypic costimulatory receptor in a subset of HCMV-specific CD4⁺ T lymphocytes and thus may have a role in the response against infected HLA class II⁺ cells displaying NKG2D ligands.