Cytomegalovirus-Induced Expression of CD244 after Liver Transplantation Is Associated with CD8+ T Cell Hyporesponsiveness to Alloantigen

The chronic presence of viral Ags can induce T cell exhaustion, which is characterized by upregulation of coinhibitory receptors and loss of T cell function. We studied whether a similar phenomenon occurs after liver transplantation (LTx), when there is continuous exposure to alloantigen. Expression of coinhibitory receptors on circulating CD4(+) and CD8(+) T cells was analyzed longitudinally in 19 patients until 6 mo after LTx and cross-sectionally in 38 patients late (1-12 y) after LTx. Expression of the coinhibitory receptors CD160 and CD244 on circulating CD8(+) T cells was already higher 6 mo after LTx compared with pre-LTx, and the elevated expression was sustained late after LTx, with CD244 showing the more prominent increase. The strongest upregulation of CD244 on circulating CD8(+) T cells was observed in patients who experienced CMV infection after LTx. CMV infection also was associated with reduced CD8(+) T cell proliferation and cytotoxic degranulation in response to alloantigen late after LTx. Purified CD244(+)CD8(+) T cells from LTx patients showed lower proliferative responses to alloantigen, as well as to polyclonal stimulation, than did their CD244(-) counterparts. In addition, the CD244(+)CD8(+) T cell population contained the majority of CMV peptide-loaded MHC class I tetramer-binding cells. In conclusion, CMV infection after LTx, rather than persistence of alloantigen, induces the accumulation of dysfunctional CD244(+)CD8(+) T cells in the circulation that persist long-term, resulting in reduced frequencies of circulating alloreactive CD8(+) T cells. These results suggest that CMV infection restrains CD8(+) T cell alloresponses after LTx.