Purpose Classically, NKG2 receptors are associated with cytotoxic cells, such as NK and CD8+ T lymphocytes. However, NKG2A has been recently found on activated T-helper (TH) cells, presenting the possibility of differential expression between TH1 and TH2 subtypes. Given the importance of the balance between TH1 and TH2 cells in critical illnesses such as asthma and ARDS, this finding could be significant as these are the only TH receptors known to bind MHC class I complexes. To examine the expression of NKG2 receptors on TH1 and TH2 cells in quiescence and with activation.
Methods Using a density gradient method, the mononuclear cell (MNC) layer was isolated from the peripheral blood of 5 healthy volunteers. TH1 and TH2 cells were isolated from the MNC fractions using a negative cell selection technique. Each cell isolate was split and half was activated for 4 hours with PMA, ionomycin, and brefeldin A. Flow cytometry was performed on the activated and non-activated samples.
Results All isolates were pure CD3+CD4+ cells (SE: 98.8 0.4%) with no evidence of CD8+ or CD56+ contamination. We found moderate levels of NKG2C positivism on quiescent TH2 cells (14.7 4%) but little NKG2A. After activation, we found significantly increased expression of NKG2A (12.9 7.3%; p = 0.03) and decreased NKG2C (7.2 3.3%; p = 0.26) on TH2 cells, in addition to cells newly positive for CD56 (27.6 16.6%; p = 0.01). The degree of TH2 NKG2 expression with activation varied between individuals but was reproducible within an individual. There was little notable expression of either NKG2 receptor on TH1 cells before or after activation.
Conclusions These data suggest that the earlier finding of NKG2 receptors on activated TH cells is due to TH2 up-regulation of several NK-like surface markers. This implies that these cells have some role in cytotoxicity. Intriguing also is the dramatic inter-individual differences in NKG2 expression levels. Elucidation of whether this is genetically-driven or a function of NKG2-switching among unmeasured subtypes is a crucial next step and could lead to important new understanding of the pathophysiology of TH1/2 balance-related diseases like asthma and ARDS.
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