TIGIT limits immune pathology during viral infections

Schorer, Michelle; Rakebrandt, Nikolas; Lambert, Katharina; Hunziker, Annika; Pallmer, Katharina; Oxenius, Annette; Kipar, Anja; Stertz, Silke; Joller, Nicole

doi:10.1038/s41467-020-15025-1

Cited by 54 publications

(45 citation statements)

References 68 publications

(95 reference statements)

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“…However, excessive immune responses to influenza virus can lead cytokine storms, which cause pathological damage to tissues. Immune checkpoints can limit such immune pathology; for example, TIGIT can reduce immune-mediated tissue damage in an IL-10-dependent manner during acute virus infection [81]. The negative regulatory function of T-cells was found to be improved in a mutant mouse with a deletion in the distal cytoplasmic domain of TIM-3.…”

Section: Immune Checkpoints In Influenzamentioning

confidence: 99%

Immune Checkpoints in Viral Infections

Cai

Liu

Zhong

et al. 2020

Viruses

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As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.

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Section: Immune Checkpoints In Influenzamentioning

confidence: 99%

Immune Checkpoints in Viral Infections

Cai

Liu

Zhong

et al. 2020

Viruses

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“…Indeed, preclinical studies have found that ARBs, including losartan, can prevent COVID-19 pulmonary injuries, suggesting that ANG II/AT-1R signaling drives the immune defects associated with SARS-CoV-2 (70). Moreover, as the TIGIT pathway has been found to promote immune dysregulation in response to many viral infections, it is likely that SARS-CoV-2 may manipulate this EM to evade detection (10). Indeed, elevated levels of IL-10, a TIGIT-signaling cytokine, have been documented in COVID-19 patients, suggesting that SARS-CoV-2 exploits these proteins to cover its molecular signatures (Figure 4) (94).…”

Section: Excess Ang II Promotes Premature Ec Senescence Along With Dymentioning

confidence: 99%

“…In addition, faulty coagulation, associated with deep venous thrombosis (DVT) and pulmonary embolism (PE), has further complicated the management of this syndrome (7). These prior findings have been replicated in relation to SARS-CoV-2 and seem to precede the development of critical illness, suggesting that defective immunity may play a major role in this disease (8)(9)(10). Indeed, as in avian influenza, the upregulation of NK cell, and CTC exhaustion GRAPHICAL ABSTRACT | The SARS-CoV-2 virus engages the angiotensin-converting enzyme-2 (ACE-2) protein, displacing its physiological ligand.…”

Section: Introductionmentioning

confidence: 99%

Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis

et al. 2020

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Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).

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“…Nevertheless, at very high antigen doses, T cells revert to Th2 differentiation, potentially due to the susceptibility of Th1 cells to activation induced cell death (AICD) (47,48). AICD of Th1 cells might also contribute to biased Tfh generation at the higher end of TCR signal strength during Clone-13 infection (49,50).…”

Section: Discussionmentioning

confidence: 99%

Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

Künzli

Reuther

Pinschewer

et al. 2020

Preprint

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A hallmark of the adaptive immune response is the ability of CD4 T cells to differentiate into a variety of pathogen appropriate and specialized effector subsets. A long-standing question in CD4 T cell biology is whether the strength of TCR signals can instruct one Th cell fate over another. The contribution of TCR signal strength to the development of Th1 and T follicular helper (Tfh) cells has been particularly difficult to resolve, with conflicting results reported in a variety of models. Although cumulative TCR signal strength can be modulated by the infection specific environment, whether or not TCR signal strength plays a dominant role in Th1 versus Tfh cell fate decisions across distinct infectious contexts is not known. Here we characterized the differentiation of CD4 TCR transgenic T cells responding to a panel of recombinant wild type or altered peptide ligand lymphocytic choriomeningitis viruses (LCMV) derived from acute and chronic parental strains. We found that while TCR signal strength positively regulates T cell expansion in both infection settings, it exerts opposite and hierarchical effects on the balance of Th1 and Tfh cells generated in response to acute versus persistent infection. The observation that weakly activated T cells, which comprise up to fifty percent of an endogenous CD4 T cell response, support the development of Th1 effectors highlights the possibility that they may resist functional inactivation during chronic infection. We anticipate that the panel of variant ligands and recombinant viruses described herein will be a valuable tool for immunologists investigating a wide range of CD4 T cell responses.

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TIGIT limits immune pathology during viral infections

Cited by 54 publications

References 68 publications

Immune Checkpoints in Viral Infections

Immune Checkpoints in Viral Infections

Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis

Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

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