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

Abstract

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.

Potential Beneficial Effects of Cytomegalovirus Infection after Transplantation

“…Increased numbers of circulating terminally differentiated CD8 + T cells expressing co-inhibitory receptors is another feature shared by CMV infection ( 53 , 67 ) and operational tolerance ( 56 ) after LTx, again suggesting a possible association. Finally, comparison of gene expression patterns in circulating leukocytes between tolerant and non-tolerant LTx recipients revealed over-expression of NK-cell-related genes in tolerant patients.…”

“…Although Vδ1 +γδ T cells under certain conditions may have immune-regulatory properties ( 72 , 73 ), it is as yet unknown whether they can contribute to liver graft acceptance. However, the massive peripheral expansion of terminally differentiated CD8 + T cells expressing co-inhibitory receptors upon CMV infection after LTx may contribute to reduced T-cell alloreactivity to organ grafts, since these cells show impaired functional responses to allo-antigens ( 53 , 67 ) (Figure 1 ). In addition, as terminally differentiated CD8 + T cells poorly infiltrate in organ grafts, they might not contribute to graft rejection even when functionally competent to respond to allo-antigens ( 53 , 74 ).…”

The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment

“…In humans, CD244 expression has been shown to be increased on CD8+ T cells in chronic infection ( 15 , 46 – 51 ). In these infections, CD244 expression correlates with CD8+CD45RA+CCR7- effector or effector memory subtypes ( 46 , 47 ).…”

“…In humans, CD244 expression has been shown to be increased on CD8+ T cells in chronic infection ( 15 , 46 – 51 ). In these infections, CD244 expression correlates with CD8+CD45RA+CCR7- effector or effector memory subtypes ( 46 , 47 ). CD244 expression is higher on virus-specific CD8+ T cells in patients with chronic infection than with acute infection and correlates with PD1 expression ( 15 , 47 ).…”

“…Corresponding to inhibitory signaling in NK cells, CD244 demonstrates an inhibitory function when expressed at higher concentrations on CD8+ T cells that demonstrate an exhausted phenotype in chronic viral infection and cancer ( 10 , 11 , 46 , 47 , 50 , 52 , 76 ). Furthermore, in MDSCs from tumor-bearing mice, CD244 expression correlates with suppression of antigen-specific CD8+ T cell function and production of suppressive molecules, suggesting a role for CD244 signaling in the immunosuppressive function of these cells.…”