Marked T cell activation, senescence, exhaustion and skewing towards Th17 in patients with Covid-19 pneumonia
Authors: De Biasi, S., Meschiari, M., Gibellini, L., Bellinazzi, C., Borella, R., Fidanza, L.., Lo Tartaro, D., Mattioli, M., Paolini, A., Menozzi, M., Milić, J., Franceschi, G., Fantini, R., Tonelli, R., Sita, M., Sarti, M., Clini, E., Girardis, M., Guaraldi G., Mussini, C., Cossarizza, A.
Journal/ Pre-Print: Nature Research group, under review
This study focused on characterizing peripheral blood CD4+ and CD8+ T cells of 21 lymphopenic patients that developed pneumonia (13 age/sex-matched healthy individuals were used as controls). Both T cell types exhibited a change in phenotype in Covid-19 patients. Overall, naïve and central memory T cells were found in lower frequencies, while an increase in activated/senescent/exhausted cells was observed. Among CD4+ T cells, Tregs were found in higher frequencies in Covid-19 patients, which could be interpreted as a possible contributing factor for deteriorated adaptive T cell immunity in severe cases. In face of significant higher levels of cytokines in the serum of infected individuals, further characterization of T cell function revealed a significant increase in the frequencies of T cells able to produce IL-17. As this cytokine is able to promote the recruitment of neutrophils, which are currently linked to higher severity in Covid-19 patients, the authors suggest anti-IL-17 treatment as a possible novel and efficient therapy for Sars-Cov-2.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19
Treat of SARS-CoV2/COVID19 positive individuals
· Patient Case study
Strengths and limitations of the paper
Novelty: Identification of a Th17 skewed phenotype in CD4+ T cells from Covid-19 patients
Standing in the field: Supports the role of neutrophils, recruited by T-cell derived IL-17, in the cytokine storm observed in severe cases of Covid-19
Appropriate statistics: High-dimensional data analysis was done following referenced papers; other analyses were submitted to Mann-Whitney tests, but there is no mention of normality tests having been carried out previously.
Viral model used: n/a
Translatability: Suggests anti-IL-17 as a possible therapeutic approach
Main limitations: Group of only 21 COVID-19 patients and limited to the ones that developed pneumonia: patient age median = 61, mostly men.
Patients are a mix: some had underlying conditions, some didn’t. This is not clearly discriminated by the study when discussing the results, and could potentially obfuscate readouts.
Gating strategies/technical details are addressed not just in the methods, but also along the results, making the paper message less clear than it could be.
Although phenotypical differences observed in CD4+ or CD8+ T cells were statistically significant, biologically relevance was not clear (very small percentages for some subsets). The markers used to determine each subset are also a bit vague. Exhaustion and senescence, for example, are treated as part of the same phenomenon, which is now known not to be the case.
Figure 5, the main figure on which the paper’s conclusions are based, is very difficult to interpret because of the way it is displayed.
On its own, the paper does not provide sufficient evidence to support a therapeutic strategy using anti-IL-17 and further clinical and functional studies are required to validate this concept.