Impaired Cytotoxic CD8⁺T Cell Response in Elderly COVID-19 Patients

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8+ T cell subsets. PD-1-expressing CD8+ T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development. IMPORTANCE Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.

Maturation of T and B Lymphocytes in the Assessment of the Immune Status in COVID-19 Patients

“…Gong F. et al [34] have also shown that SARS-CoV-2-specific CD8+ T-cells typically had a more effector phenotype. Westmeier, J. et al [36] found that SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, characterized by the simultaneous production of granzyme A and B as well as perforin. Moreover, they indicated that CD8+ cells were not functionally exhausted.…”

Co-infection in COVID-19, a cohort study

“…4 Elderly COVID-19 patients have impaired Cytotoxic CD8 + T Cell Responses, which may make them highly risk for infection. 5 A. baumannii is a common pathogen in Intensive Care Units (ICU) and evolves rapidly to be resistant to many antibiotics and should be seriously considered for critical COVID-19 patients. 6 In summary, we carried out an extensive pathogen screening in a COVID-19 cohort.…”

Akt-Fas to Quell Aberrant T Cell Differentiation and Apoptosis in Covid-19

“…However, the CD8+ T cells of the elderly group (ages 80–96) did not upregulate the cytotoxic markers Granzyme B and Perforin as the younger group did (ages 29–79), indicating age-related exhaustion ( 15 ). They conclude PD-1 expressing CD8+ cells should not be ‘misclassified’ as exhausted, however they state that PD-1 therapy may improve virus control (presumably in the elderly group) but also may “exaggerate the immunopathology in the lungs and other organs” ( 15 ). We agree with this therapy in regard to aged patients but also propose that cytotoxic function may be overexuberant in younger populations and that withholding differentiation may, to an extent, temper Granzyme and Perforin expression.…”

“…Zheng et al did not find lymphopenia in their cohort, however they noted that a non-exhausted subgroup of PD-1- CTLA4- TIGIT- CD8+ T cells were significantly reduced in percentage in patients with severe Covid-19 compared to mild and moderate ( 14 ). Westmeier et al sought to characterize the proteins that cause cytotoxicity and possibly immunopathological organ damage, and they found in young (29–79) patients CD8+ T cells activated ex vivo following convalescence produced granzymes A, B, and perforin at greater levels than healthy donors despite expressing PD-1, suggesting the exhaustion was not functional despite PD-1 expression ( 15 ). However, the CD8+ T cells of the elderly group (ages 80–96) did not upregulate the cytotoxic markers Granzyme B and Perforin as the younger group did (ages 29–79), indicating age-related exhaustion ( 15 ).…”

“…Westmeier et al sought to characterize the proteins that cause cytotoxicity and possibly immunopathological organ damage, and they found in young (29–79) patients CD8+ T cells activated ex vivo following convalescence produced granzymes A, B, and perforin at greater levels than healthy donors despite expressing PD-1, suggesting the exhaustion was not functional despite PD-1 expression ( 15 ). However, the CD8+ T cells of the elderly group (ages 80–96) did not upregulate the cytotoxic markers Granzyme B and Perforin as the younger group did (ages 29–79), indicating age-related exhaustion ( 15 ). They conclude PD-1 expressing CD8+ cells should not be ‘misclassified’ as exhausted, however they state that PD-1 therapy may improve virus control (presumably in the elderly group) but also may “exaggerate the immunopathology in the lungs and other organs” ( 15 ).…”