Polyfunctional T-Cell Signatures to Predict Protection from Cytomegalovirus after Lung Transplantation

Abstract

Rationale: Cytomegalovirus (CMV), which is one of the most common infections after lung transplantation, is associated with chronic lung allograft dysfunction and worse post-transplantation survival. Current approaches for at-risk patients include a fixed duration of antiviral prophylaxis despite the associated cost and side effects.Objectives: We sought to identify a specific immunologic signature that predicted protection from subsequent CMV.Methods: CMV-seropositive lung transplantation recipients were included in the discovery (n = 43) and validation (n = 28) cohorts. Polyfunctional CMV-specific immunity was assessed by stimulating peripheral blood mononuclear cells with CMV pp65 or IE-1 peptide pools and then by measuring T-cell expression of CD107a, IFN-g, tumor necrosis factor-a (TNF-a), and IL-2. Recipients were prospectively monitored for subsequent viremia. A Cox proportional hazards regression model that considered cytokine responses individually and in combination was used to create a predictive model for protection from CMV reactivation. This model was then applied to the validation cohort.Measurements and Main Results: Using the discovery cohort, we identified a specific combination of polyfunctional T-cell subsets to pp65 that predicted protection from subsequent CMV viremia (concordance index 0.88 [SE, 0.087]

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

“…This is in general consistent with previous observations, where CD4 T cells responding to viral peptides produced IFN γ and other cytokines and mobilized CD107a/b to surface . A polyfunctional response has been associated with efficient control of viral infections, including HCMV, HIV‐1, and hepatitis C , and might also be important in the response to HHV‐6B. In addition to confirming previous observations of degranulation , we found evidence of intracellular storage of granzyme B and observed antigen‐specific cytotoxic activity, both highlighting a direct effector role of CD4 T cells in the control of HHV‐6B, as previously suggested .…”

Proteome‐wide analysis of T‐cell response to BK polyomavirus in healthy virus carriers and kidney transplant recipients reveals a unique transcriptional and functional profile

“…This analysis clearly showed that CD8 + T-cell responses in healthy individuals were predominantly directed towards LTA and STA, while VP1, VP2 and VP3 antigens were comparably less frequently recognised ( Figure 1a). [12][13][14] To further expand the functional profiling of BKV T cells, we assessed polyfunctional capability of antigen-specific T cells from both healthy individuals and kidney transplant recipients. Extension of BKVspecific T-cell profiling to kidney transplant recipients revealed that patients with viral load of >1 10 3 copies per mL in plasma (referred to as high viraemic recipients) had significantly reduced CD8 + and CD4 + T-cell reactivity against STA and/or LTA antigens when compared to healthy individuals (Figure 1a and b).…”

“…Previous studies have highlighted the importance of the polyfunctional profile of antigen-specific T cells and its impact on disease outcomes. [12][13][14] To further expand the functional profiling of BKV T cells, we assessed polyfunctional capability of antigen-specific T cells from both healthy individuals and kidney transplant recipients. In vitro expanded BKVspecific T cells were assessed for the production of IFN-c, TNF, CD107a and IL-2 by intracellular cytokine staining following stimulation with HLA class I-restricted BKV-specific T-cell epitopes (Figure 2a).…”

Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

“…Given that polyfunctional T cells confer a more effective immune response to infections (Yamamoto et al, 2009; Boyd et al, 2015; Snyder et al, 2016), it is important to investigate the impact of aging on T cell polyfunctionality. Van Epps et al demonstrated enhanced polyfunctionality in CD8 + T EM cell subsets in older individuals, but both CD4 + and CD8 + T CM cells exhibited an age-associated decline in polyfunctionality (Van Epps et al, 2014).…”