Complement activation induces excessive T cell cytotoxicity in severe COVID-19

Abstract

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated, CD16 + T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16 + T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16 + T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16 + cytotoxic T cells. Proportions of activated CD16 + T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

Understanding the Effects of Age and T-Cell Differentiation on COVID-19 Severity: Implicating a Fas/FasL-mediated Feed-Forward Controller of T-Cell Differentiation

“…Given the possible frequency of Covid-19 reinfection and rechallenge, the model can be updated to incorporate T cell differentiation and effector function conferred by reinfection. Based upon data showing a retraction of the Tn repertoire following infection by Townsend et al, and Phetsouphanh et al, we can speculate regarding a possible “T cell depletion dependent enhancement” as the stimulated repertoire (which includes the T cells specific to SARS-Cov-2 epitopes, those activated by a bystander effect, and those also stimulated superantigenically and by complement) has lost a proportion of its Tn and is thereby able to quickly differentiate into T cell Effectors since there is no CD95L sink that the CD95 expression on Tn and Tscm offer ( 30 – 32 , 54 ). This effect would be more evident in the aged 60+, who have significant reductions in CD8+ Tn proportions following SARS Cov-2 infection, due to the bystander, complement, and superantigen-induced excessive stimulation ( 30 – 32 , 34 ).…”

“…Based upon data showing a retraction of the Tn repertoire following infection by Townsend et al, and Phetsouphanh et al, we can speculate regarding a possible “T cell depletion dependent enhancement” as the stimulated repertoire (which includes the T cells specific to SARS-Cov-2 epitopes, those activated by a bystander effect, and those also stimulated superantigenically and by complement) has lost a proportion of its Tn and is thereby able to quickly differentiate into T cell Effectors since there is no CD95L sink that the CD95 expression on Tn and Tscm offer ( 30 – 32 , 54 ). This effect would be more evident in the aged 60+, who have significant reductions in CD8+ Tn proportions following SARS Cov-2 infection, due to the bystander, complement, and superantigen-induced excessive stimulation ( 30 – 32 , 34 ). Of course, primed T-cells such as those from vaccination are capable of exerting earlier control of infection ( 55 ); and indeed, early CD8 bystander activation is associated with better control of infection ( 33 ), so we anticipate a degree of protection conferred from vaccination when the individual has a paucity of naïve T cells, such as in Figure 1C .…”

“…In cases where early control is not accomplished, T cell memory could contribute to an overexuberant response ( 12 , 37 , 38 ). Indeed, exuberant CD8+ T-cell mediated pathology has been documented in infections like RSV and SARS-CoV-2 alike ( 32 , 56 , 57 ). Memory CD8+ responses have been shown to exert immunopathology and severe disease in murine models of RSV ( 56 ).…”

“…T-cell differentiation and acquisition of effector function is accomplished via Feed-forward control. In Covid-19, there is nonspecific and possibly bystander cytotoxic CD8+ T-cell activation which may be a double-edged sword, exerting damage to tissues and vital organs like the lung and pancreas ( 14 , 30 – 32 , 52 , 53 , 60 ). The FFL proposed here gives a mechanism for both the exuberant T-cell response observed in severe cases and the protective effect of Tn ( 12 , 23 , 32 , 37 ).…”

“…Indeed, André et al propose blocking Fas-mediated death via a pan caspase inhibitor Q-VD ( 28 ). Finally, given the differentiation and depreciation of the Tn pool from infection likely due to the overshooting T-cell stimulation from SARS-Cov-2’s cryptic ( 29 ) accumulation of superantigenic biomass ( 12 , 30 , 31 ), T cell activation via complement ( 32 ), and bystander activation ( 33 ), we can use the model to anticipate the possibility of worsening disease upon reinfection in cases where there is not adequate early control and a highly differentiated T cell repertoire ( 34 ). This does not mean all reinfections will be worse, rather that they will be worse when the parameters of this feed-forward model are met.…”