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Increased Expression of Multiple Co-Inhibitory Molecules on Malaria-Induced CD8⁺ T Cells Are Associated With Increased Function Instead of Exhaustion.

ABSTRACT: Activated cytotoxic CD8⁺ T cells can selectively kill target cells in an antigen-specific manner. However, their prolonged activation often has detrimental effects on tissue homeostasis and function. Indeed, overwhelming cytotoxic activity of CD8⁺ T cells can drive immunopathology, and therefore, the extent and duration of CD8⁺ T cell effector function needs to be tightly regulated. One way to regulate CD8⁺ T cell function is their suppression through engagement of co-inhibitory molecules to their cognate ligands (e.g., LAG-3, PD-1, TIM-3, TIGIT and CTLA-4). During chronic antigen exposure, the expression of co-inhibitory molecules is associated with a loss of T cell function, termed T cell exhaustion and blockade of co-inhibitory pathways often restores T cell function. We addressed the effect of co-inhibitory molecule expression on CD8⁺ T cell function during acute antigen exposure using experimental malaria. To this end, we infected OT-I mice with a transgenic P. berghei ANKA strain that expresses ovalbumin (PbTG), which enables the characterization of antigen-specific CD8⁺ T cell responses. We then compared antigen-specific CD8⁺ T cell populations expressing different levels of the co-inhibitory molecules. High expression of LAG-3 correlated with high expression of PD-1, TIGIT, TIM-3 and CTLA-4. Contrary to what has been described during chronic antigen exposure, antigen-specific CD8⁺ T cells with the highest expression of LAG-3 appeared to be fully functional during acute malaria. We evaluated this by measuring IFN-γ, Granzyme B and Perforin production and confirmed the results by employing a newly developed T cell cytotoxicity assay. We found that LAG-3^high CD8⁺ T cells are more cytotoxic than LAG-3^low or activated but LAG-3^neg CD8⁺ T cells. In conclusion, our data imply that expression of co-inhibitory molecules in acute malaria is not necessarily associated with functional exhaustion but may be associated with an overwhelming T cell activation. Taken together, our findings shed new light on the induction of co-inhibitory molecules during acute T cell activation with ramifications for immunomodulatory therapies targeting these molecules in acute infectious diseases.

SUBMITTER: Brandi J

PROVIDER: S-EPMC9301332 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Increased Expression of Multiple Co-Inhibitory Molecules on Malaria-Induced CD8+ T Cells Are Associated With Increased Function Instead of Exhaustion.

Brandi Johannes J Riehn Mathias M Hadjilaou Alexandros A Jacobs Thomas T

Frontiers in immunology 20220707

Activated cytotoxic CD8+ T cells can selectively kill target cells in an antigen-specific manner. However, their prolonged activation often has detrimental effects on tissue homeostasis and function. Indeed, overwhelming cytotoxic activity of CD8+ T cells can drive immunopathology, and therefore, the extent and duration of CD8+ T cell effector function needs to be tightly regulated. One way to regulate CD8+ T cell function is their suppression through ...[more]

PMID: 35874786

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Project description:BackgroundCoronavirus disease 2019 (COVID-19) is pandemic. It is critical to identify COVID-19 patients who are most likely to develop a severe disease. This study was designed to determine the clinical and epidemiological features of COVID-19 patients associated with the development of pneumonia and factors associated with disease progression.MethodsSeventy consecutive patients with etiologically confirmed COVID-19 admitted to PLA General Hospital in Beijing, China from December 27, 2019 to March 12, 2020 were enrolled in this study and followed-up to March 16, 2020. Differences in clinical and laboratory findings between COVID-19 patients with pneumonia and those without were determined by the χ2 test or the Fisher exact test (categorical variables) and independent group t test or Mann-Whitney U test (continuous variables). The Cox proportional hazard model and Generalized Estimating Equations were applied to evaluate factors that predicted the progression of COVID-19.ResultsThe mean incubation was 8.67 (95% confidence interval, 6.78-10.56) days. Mean duration from the first test severe acute respiratory syndrome coronavirus 2-positive to conversion was 11.38 (9.86-12.90) days. Compared to pneumonia-free patients, pneumonia patients were 16.5 years older and had higher frequencies of having hypertension, fever, and cough and higher circulating levels of neutrophil proportion, interleukin-6, low count (< 190/µl) of CD8+ T cells, and neutrophil/lymphocyte ratio. Thirteen patients deteriorated during hospitalization. Cox regression analysis indicated that older age and higher serum levels of interleukin-6, C-reactive protein, procalcitonin, and lactate at admission significantly predicted the progression of COVID-19. During hospitalization, circulating counts of T lymphocytes, CD4+ T cells, and CD8+ T cells were lower, whereas neutrophil proportion, neutrophil/lymphocyte ratio, and the circulating levels of interleukin-6, C-reactive protein, and procalcitonin were higher, in pneumonia patients than in pneumonia-free patients. CD8+ lymphocyte count in pneumonia patients did not recover when discharged.ConclusionsOlder age and higher levels of C-reactive protein, procalcitionin, interleukin-6, and lactate might predict COVID-19 progression. T lymphocyte, especially CD8+ cell-mediated immunity is critical in recovery of COVID-19. This study may help in predicting disease progression and designing immunotherapy for COVID-19.

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Increased Expression of Multiple Co-Inhibitory Molecules on Malaria-Induced CD8⁺ T Cells Are Associated With Increased Function Instead of Exhaustion.

Publications

Increased Expression of Multiple Co-Inhibitory Molecules on Malaria-Induced CD8<sup>+</sup> T Cells Are Associated With Increased Function Instead of Exhaustion.

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