Comorbid illnesses are associated with altered adaptive immune responses to SARS-CoV-2
Krystle K.Q. Yu, … , Galit Alter, Chetan Seshadri
Krystle K.Q. Yu, … , Galit Alter, Chetan Seshadri
Published February 23, 2021
Citation Information: JCI Insight. 2021;6(6):e146242. https://doi.org/10.1172/jci.insight.146242.
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Research Article COVID-19 Immunology

Comorbid illnesses are associated with altered adaptive immune responses to SARS-CoV-2

Abstract

Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multiparameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n = 20) or not hospitalized (n = 40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4+ T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4+ T cells and antibodies targeting the S1 domain of spike among subjects who were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2, which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19.

Authors

Krystle K.Q. Yu, Stephanie Fischinger, Malisa T. Smith, Caroline Atyeo, Deniz Cizmeci, Caitlin R. Wolf, Erik D. Layton, Jennifer K. Logue, Melissa S. Aguilar, Kiel Shuey, Carolin Loos, Jingyou Yu, Nicholas Franko, Robert Y. Choi, Anna Wald, Dan H. Barouch, David M. Koelle, Douglas Lauffenburger, Helen Y. Chu, Galit Alter, Chetan Seshadri

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Figure 5

CD8+ T cell responses to SARS-CoV-2 structural antigens are not associated with hospitalization.

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CD8+ T cell responses to SARS-CoV-2 structural antigens are not associat...
(A) Intracellular cytokine staining was used to profile the functions of CD8+ T cells specific for the S1 and S2 domains of spike, nucleocapsid (N), and envelope small membrane protein (E). Results of COMPASS are displayed as a heatmap in which rows represent study subjects and columns represent CD8+ T cell functional subsets. The depth of shading within the heatmap represents the probability of detecting a response above background. In the column legend, white indicates absence and black/gray indicates presence of a function. (B) Background subtracted magnitudes of CD8+ T cell responses stratified by the presence of IFN-γ. A single outlier is not displayed for S2 and N. (C) Representative bivariate flow cytometry plots showing the expression of IFN-γ and CD107a following stimulation. (D) Cells expressing any of the functional profiles identified by COMPASS were aggregated across all subjects prior to UMAP. (E) Magnitudes of CD8+ T cells expressing CD107a in the absence of other functions. (F) The CD8+ T cell functionality score (FS) as determined by COMPASS. (G) Two-way correlations of FS were calculated between stimulations. Colored squares indicated a statistically significant correlation (P < 0.05). (H–J) For each stimulation, we examined the association with age (H), sex (I), and hospitalization status (J). Black lines on the scatter plots represent best fit linear regression lines, and the gray-shaded areas represent the 95% CI of the predicted means. Data were analyzed using Wilcoxon signed-rank tests (B, E, and F) and Mann-Whitney U tests (I and J) and were corrected for multiple hypothesis testing using the Bonferroni method. Median, 25th, and 75th quartiles are indicated for violin plots. If not shown, P values were not significant. n = 60 in all panels.