Emergence of Human CMV-induced NKG2C+ NK cells is Associated with CD8+ T cell Recovery following Allogeneic HCT.

Cytomegalovirus infection is associated with the expansion of a mature NKG2C+FcεR1γ- NK population, which is distinct and thought to derive from the less differentiated NKG2A+ NK population. The exact mechanism underlying the emergence of NKG2C+ NK cells, however, remains unknown. Allogeneic hematopoietic cell transplantation (HCT) provides an opportunity to longitudinally study lymphocyte recovery in the setting of CMV reactivation, particularly in patients receiving T cell-depleted (TCD) allografts, in whom lymphocyte populations recover with variable rapidity. We analyzed peripheral blood lymphocytes at serial timepoints from 119 patients following infusion of their TCD allograft and compared immune recovery to samples obtained from recipients of T cell-replete (T-replete) (n=96) or double umbilical cord blood (DUCB) (n=52) allografts. NKG2C+ NK cells were detected in 92% of TCD-HCT patients who experienced CMV reactivation (n=45/49). While NKG2A+ cells were routinely identifiable early post-HCT, NKG2C+ NK cells were identified only after T cells could be detected. T cell reconstitution occurred at variable times post-HCT among patients and was comprised predominantly of CD8+ T cells. In patients with CMV reactivation, TCD-HCT patients expressed significantly higher frequencies of NKG2C+ and CD56neg NK cells compared to T-replete-HCT or DUCB transplant patients. NKG2C+ NK cells following TCD-HCT were CD57+FcεR1γ+ and degranulated significantly more in response to target cells compared to the adaptive NKG2C+CD57+FcεR1γ- NK cell population. We conclude that the presence of circulating T cells is associated with the expansion of the CMV-induced NKG2C+ NK cell population, a potentially novel example of developmental cooperation between lymphocyte populations in response to viral infection.