Human cytomegalovirus expands a CD8+ T cell population with loss of BCL11B expression and gain of NK cell identity

Sci Immunol. 2021 Sep 24;6(63):eabe6968. doi: 10.1126/sciimmunol.abe6968. Epub 2021 Sep 24.


CD8+ T cells not only are critical mediators of adaptive immunity but also may exhibit innate-like properties such as surface expression of NKG2C, an activating receptor typically associated with natural killer (NK) cells. We demonstrate that, similar to NK cells, NKG2C+TCRαβ+CD8+ T cells are associated with prior human cytomegalovirus (HCMV) exposure. In addition to expressing several NK cell markers such as CD56 and KIR, NKG2C+CD8+ T cells are oligoclonal and do not up-regulate PD-1 even in response to persistent activation. Furthermore, we found that NKG2C+CD8+ T cells from some individuals exhibited strong effector function against leukemia cells and HCMV-infected fibroblasts, which was dictated by both NKG2C and TCR specificity. Transcriptomic analysis revealed that the transcription factor BCL11B, a regulator of T cell developmental fate, is down-regulated in NKG2C+CD8+ T cells when compared with conventional NKG2CCD8+ T cells. BCL11B deletion in conventional CD8+ T cells resulted in the emergence of a similar innate-like CD56+CD94+DAP12+NKG2C+CD45RA+CCR7PD-1−/low T cell population with activity against HLA-E+ targets. On the basis of their intrinsic capacity to recognize diseased cells coupled with lack of PD-1 induction, NKG2C+CD8+ T cells represent a lymphocyte population that resides at the boundary between innate and adaptive immunity, presenting an attractive alternative for cellular therapy, including CAR T cell–based therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • Cytomegalovirus / immunology*
  • Humans
  • Killer Cells, Natural / immunology*
  • Repressor Proteins / genetics*
  • Repressor Proteins / immunology
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / immunology


  • BCL11B protein, human
  • Repressor Proteins
  • Tumor Suppressor Proteins