CMV-Responsive CD4 T Cells Have a Stable Cytotoxic Phenotype Over the First Year Post-Transplant in Patients Without Evidence of CMV Viremia

Abstract

Cytomegalovirus (CMV) infection is a known cause of morbidity and mortality in solid organ transplant recipients. While primary infection is controlled by a healthy immune system, CMV is never eradicated due to viral latency and periodic reactivation. Transplantation and associated therapies hinder immune surveillance of CMV. CD4 T cells are an important part of control of CMV reactivation. We therefore investigated how CMV impacts differentiation, functionality, and expansion of protective CD4 T cells from recipients of heart or kidney transplant in the first year post-transplant without evidence of CMV viremia. We analyzed longitudinal peripheral blood samples by flow cytometry and targeted single cell RNA sequencing coupled to T cell receptor (TCR) sequencing. At the time of transplant, CD4 T cells from CMV seropositive transplant recipients had a higher degree of immune aging than the seronegative recipients. The phenotype of CD4 T cells was stable over time. CMV-responsive CD4 T cells in our transplant cohort included a large proportion with cytotoxic potential. We used sequence analysis of TCRαβ to identify clonal expansion and found that clonally expanded CMV-responsive CD4 T cells were of a predominantly aged cytotoxic phenotype. Overall, our analyses suggest that the CD4 response to CMV is dominated by cytotoxicity and not impacted by transplantation in the first year. Our findings indicate that CMV-responsive CD4 T cells are homeostatically stable in the first year after transplantation and identify subpopulations relevant to study the role of this CD4 T cell population in post-transplant health.

Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant

“…This observation contrasts with the differentially higher levels of virus-specific T-cells detected in patients responding to treatment with HCT donor-derived CMV-specific T-cells that can also engraft post transfer. (14) There are likely multiple parameters important in identifying peripheral blood correlates of response to 3rd party VSTs including the virus being treated, the recipient immune milieu (eg baseline >50 CD4+ T-cells/uL and T cell depleted HSCT), the donor/host origin of the expanded population identified (as demonstrated in Figure 6), and the functional phenotype of these expanding T cells (as suggested by other authors (37)(38)(39). Technical limitations prevented us from analyzing these independently, so there may be critical differences in responders and nonresponders that we were unable to detect.…”

“…baseline greater than 50 CD4 + T cells/μL and TCD HCT), the donor/host origin of the expanded population identified (as demonstrated in Figure 6 ), and the functional phenotype of these expanding T cells (as suggested by other authors; refs. 37 – 39 ). Technical limitations prevented us from analyzing these independently, so there may be critical differences in responders and nonresponders that we were unable to detect.…”

Regulation of CD4 T Cell Responses by the Transcription Factor Eomesodermin

“…Eomes has been shown to impact CD4 T cell responses against diverse viral infections. For example, CD4 T cell responses against Human Immunodeficiency Virus (HIV), Cytomegalovirus (CMV) and Epstein–Barr Virus (EBV), characterized by cytotoxic functions are important contributors to host defenses [ 17 , 119 , 120 ]. HIV predominantly affects and depletes CD4 T cells, leading to a gradual loss of immune fitness and susceptibility to opportunistic pathogens and cancers [ 121 ].…”