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

Abstract

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathogenesis, and it remains unclear if T cells also contribute to disease pathology. Here, we combined single-cell transcriptomics and 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. Age-dependent generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

Immune signature of patients with cardiovascular disease – in-depth immunophenotyping predicts increased risk for a severe course of COVID-19

“…These data point towards reduced antibody-dependent cellular toxicity, thereby less killing of virus-infected cells (ADCC 38 ). In contrast to Georg et al, we did not detect CD16 + activated T cells in severely infected SARS-CoV-2 CVD patients 49 . This may be due to differences in the cohorts (all-comers versus CVD patients) and medication before blood collection (Partial medication such as antibiotics or steroids compared to no medication in our study).…”

“…Consistent with and in addition to previous studies, we observed changes in the frequencies of innate immune cells like CD14 + monocytes, neutrophils, mature NK cells, and MAIT cells, as well as the adaptive immune cells CD4 + CD8 + , CD8 + naïve and central memory T cells,  T cells, early-like effector memory CD4 + T cells, and naïve B cell subsets in CVD patients compared to HD 21,25,[45][46][47][48][49] . Moreover, IL-6 levels were increased in CVD patients compared to HD.…”

Allorecognition and the spectrum of kidney transplant rejection

“…In addition to FcgR expression, NK cells and myeloid cells express complement receptors CR3 and CR5 that bind to C3 degradation fragments, 200 and this binding increases the cytotoxicity of NK cells and macrophages, 201 but also of CD16A þ CD8 T cells. 202 Finally, missing self and noncomplement fixing HLA-DSA synergistically enhance NK cell activity against allogeneic endothelial cells, and this combination associated with worse allograft outcome after microvascular inflammation than presence of HLA-DSA alone. 193 Similarly, pretransplant HLA-DSA and missing self are independent and cumulative risk factors for the occurrence of microvascular inflammation after transplantation, and for the development of transplant glomerulopathy after the diagnosis of microvascular inflammation.…”

Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models

“…This heightened activation, characterized by overactivation, depletion, or apoptosis sensitivity, is identifiable through various cell surface markers, including CD38, Human Leukocyte Antigen-DR isotype (HLA-DR), programmed cell death 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and natural killer (NK) cell receptor A (NKG2A). These activated T cells are closely linked to the development of severe COVID-19 (Du et al, 2021;Georg et al, 2022;Zheng et al, 2020), as supported by numerous animal models. Zheng et al (2021a) observed a significant increase in T cell C-X-C motif chemokine receptor 3 (CXCR3) and CD38 expression in the lung tissues of elderly macaques infected with SARS-CoV-2, indicative of both activation and inflammation and potentially valuable for predicting severe COVID-19.…”