Differential CMV-Specific CD8+ Effector T Cell Responses in the Lung Allograft Predominate over the Blood during Human Primary Infection

Pipeling, Matthew R.; West, Erin E.; Osborne, Christine; Whitlock, Amanda B.; Dropulic, Lesia; Willett, Matthew; Forman, Michael; Valsamakis, Alexandra; Orens, Jonathan B.; Möller, David R.; Lechtzin, Noah; Migueles, Stephen A.; Connors, Mark; McDyer, John F.

doi:10.4049/jimmunol.181.1.546

Cited by 34 publications

(34 citation statements)

References 58 publications

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“…Thus, it is concluded that the effects of CY therapy in MCMV-infected mice extend beyond early increased viral replication from transient immunosuppression. These observations are also consistent with human models of primary CMV infection, such as our studies in lung transplant where it was demonstrated that the magnitude of expansion of CMV-specific T cells in the lung does not necessarily correlate with BAL viral load levels (32).…”

Section: Discussionsupporting

confidence: 89%

Hyperexpansion of Functional Viral-Specific CD8+ T Cells in Lymphopenia-Associated MCMV Pneumonitis

et al. 2015

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Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in immunocompromised hosts, many of whom undergo significant periods of lymphopenia. However, the impact of lymphopenia and subsequent immune reconstitution on T cell responses and pulmonary pathology are poorly understood. Using a model of primary murine CMV infection in mice treated with cyclophosphamide (CY), the relationship of CD8 + T cell reconstitution to pneumonitis pathology was studied. Female BALB/c mice were infected with murine CMV (MCMV) with/without CY on day 1 post-infection. Lung pathology and viral specific T cell responses were assessed on days 7-28. T cell lymphocyte subsets, effector responses, and MCMV specificity were assessed at baseline and after in vitro stimulation of cells with immediate-early peptide pp89. CY treatment of MCMVinfected mice resulted in interstitial pneumonitis not seen with MCMV alone. Compared to MCMV alone, on day 14, MCMV/CY mice had greater number of CD8 + T cells, a fourfold increase in absolute number of pp89 tetramer-specific CD8 + cells, and an eightfold increase in MCMV specific T cell effector responses (IFN-c; p < 0.001). This expansion was preceded by transient lymphopenia, increased viral titers, and, most strikingly, a 10-fold increased proliferative capacity in MCMV/CY mice. In the setting of CY-associated lymphopenia, concurrent MCMV infection alters immune reconstitution toward a hyperexpanded MCMV-specific CD8 + effector T cell pool that correlates with significant lung immunopathology.

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Section: Discussionsupporting

confidence: 89%

Hyperexpansion of Functional Viral-Specific CD8+ T Cells in Lymphopenia-Associated MCMV Pneumonitis

et al. 2015

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“…Therefore, a deeper understanding is required of how the level of HCMV replication is affected by the immune system, in particular by cytotoxic CD8+ T cells, which are essential for containing HCMV (14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

“…From these 67 patients, 1121 plasma samples with a mean of 17 samples per patient (range: 8-43) were collected during the follow-up at a mean interval of 25.6 days (range: 2-95), and HCMV DNA loads were measured. In parallel, a total of 758 heparinized whole-blood samples with a mean of 11.5 serial samples per patient (range: [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] were acquired prospectively at a mean interval of 31.7 days (range: 4-111) and were tested for HCMV-specific CD8+ T cell responses using the QuantiFERON R -CMV assay (Cellestis GmbH, a QIAGEN company). Of these, 598 samples (78.9%) gave a determinate result.…”

Section: Prospective Recruitment Of Patients and Acquisition Of Seriamentioning

confidence: 99%

“…Although R-LuTRs must first generate a specific T cell response when they acquire a primary HCMV infection, R+ patients display an already primed HCMV-specific T cell immunity, which might be impaired by the high-dose immunosuppressive treatment administered after lung transplantation (LuTX; Refs. [16][17][18][19]. The quality of the specific T cell response in primary HCMV infection and the kinetics with which responses recover in R+ LuTRs posttransplant determine the number of subsequent reactivation episodes and the patients' susceptibility for HCMV disease (20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Prospective Analysis of Human Cytomegalovirus DNAemia and Specific CD8+ T Cell Responses in Lung Transplant Recipients

Weseslindtner

Kerschner

Steinacher

et al. 2012

American Journal of Transplantation

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In lung transplant recipients (LuTRs), human cytomegalovirus (HCMV) DNAemia may be associated with HCMV disease and reduced survival of the allograft. Because T cells are essential for controlling HCMV replication, we investigated in this prospective study whether the kinetics of plasma HCMV DNA loads in LuTRs are associated with HCMV-specific CD8+ T cell responses, which were longitudinally assessed using a standardized assay. Sixty-seven LuTRs were monitored during the first year posttransplantation, with a mean of 17 HCMV DNA PCR quantifications and 11.5 CD8+ T cell tests performed per patient. HCMV-specific CD8+ T cell responses displayed variable kinetics in different patients, differed significantly before the onset of HCMV DNAemia in LuTRs who subsequently experienced episodes of DNAemia with high (>1000 copies/mL) and low plasma DNA levels (p = 0.0046, Fisher's exact test), and were absent before HCMV disease. In HCMV-seropositive LuTRs, highlevel DNAemia requiring preemptive therapy occurred more frequently when HCMV-specific CD8+ T cell responses fluctuated, were detected only after HCMV DNA detection, or remained undetectable (p = 0.0392, Fisher's exact test). Thus, our data indicate that HCMVspecific CD8+ T cells influence the magnitude of HCMV DNAemia episodes, and we propose that a standardized measurement of CD8+ T cell immunity might contribute to monitoring the immune status of LuTRs posttransplantation.

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“…1 in viral infections (21), especially for prevention and control of primary CMV disease after transplantation (7,22,23). However, other transplantation studies have also indicated an important role for CD4 1 T cells in CMV viral control after transplantation (24)(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

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

Snyder¹,

Chan²,

Kwon³

et al. 2016

Am J Respir Crit Care Med

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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]

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Differential CMV-Specific CD8+ Effector T Cell Responses in the Lung Allograft Predominate over the Blood during Human Primary Infection

Cited by 34 publications

References 58 publications

Hyperexpansion of Functional Viral-Specific CD8+ T Cells in Lymphopenia-Associated MCMV Pneumonitis

Hyperexpansion of Functional Viral-Specific CD8+ T Cells in Lymphopenia-Associated MCMV Pneumonitis

Prospective Analysis of Human Cytomegalovirus DNAemia and Specific CD8+ T Cell Responses in Lung Transplant Recipients

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

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