COVID-19: immune cells respond six months after infection

T cells are a part of our immune system that attack cells that have been infected with a virus or other type of pathogen

Research conducted by the UK Coronavirus Immunology Consortium (UK-CIC), Public Health England and the Manchester University NHS Foundation Trust found robust T cell responses to coronavirus six months after infection. The document “Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection” , pre-press report of preliminary data, was published in bioRxiv.org

To assess different aspects of the T cell response, such as the magnitude and response to different virus proteins, a series of analyzes was performed. According to the research, T cell responses were present in all individuals six months after infection by SARS-CoV-2. The study also found that the size of the T cell response differs between individuals. Being considerably (50%) higher in people who had experienced symptomatic disease at the time of infection, six months earlier.

Regarding robust T cell responses, Dr. Isabel Miranda Santos, Professor at the Department of Biochemistry and Immunology at the Ribeirão Preto Medical School, University of São Paulo (FMRP-USP), recalls that researchers at Rockefeller University recently showed that viral variants in the spike protein (which the virus uses for infect their host) that escape the action of neutralizing antibodies because the structure of the protein has undergone a variation in this structure to the point of affecting the ability to bind neutralizing antibodies that worked well against another viral strain. This is a problem similar to what occurs in influenza, a new vaccine has to be developed every season (influenza season).

Cellular immunity, despite being a complex piece, is potentially very significant in the COVID-19 puzzle. Although there is still no security to assert or exclude the existence of permanent immunity, the professor explains that antibodies can neutralize cell infection by the virus, but they can also facilitate viral infection if they are not properly matured in terms of their affinity for structures of the virus, including vaccine targets. “There is a history of this phenomenon, including dengue. In other words, it is not enough for the patient/the vaccine to make/induce antibodies, the antibodies need to be neutralizing and not facilitating the infection”, points out Dr. Santos

Professor Vânia Luiza Deperon Bonato, also from the Ribeirão Preto School of Medicine at the University of São Paulo (FMRP-USP), who studies factors associated with excess lung inflammation at COVID-19, clarifies that coronavirus infections do not usually induce lasting immunity. “The study of large cohorts through longitudinal analysis of individuals from different regions of the world will be crucial to conclude the extension of immunity against this pathogen. Still according to her, longitudinal analysis requires the evaluation of blood/plasma samples from each individual among the different clinical forms of COVID-19 at different and long times after recovery. It would be important to determine the titers of IgG antibodies and the frequencies of specific lymphocytes for SARS-CoV-2, antigens, for example, protein S (Spike protein, which appears to be the main target antigen), she adds.

Cellular immunity is potentially very significant because once viral infection is established, and in the presence of a high viral load, CD8 ⁺ T lymphocytes, which are cytotoxic T lymphocytes, will be crucial to eliminate/induce the death of infected cells, and with that, reduce the reservoir and viral load. According to Dr. Bonato, in most viral infections, CD4 ⁺ T lymphocytes cooperate with CD8 ⁺ T lymphocytes so that they can perform their function more efficiently. “What we have been following in the published studies is that the severe forms of COVID-19 are associated with lymphopenia, which is the reduction in the number of T CD8 ⁺ and T CD4 ⁺ lymphocytes in the circulation/in the blood and an increase in pro-inflammatory cytokines, a process described as a cytokine storm. Thus, we could think that the reduction in the number of lymphocytes could compromise the elimination of the infection”, she highlights.

Professor Bonato details, however, that studies with lung samples from patients who died had exuberant inflammation of myeloid cells (neutrophils and macrophages), and also infiltrates of CD8 ⁺ and CD4 ⁺ T lymphocytes, and that although SARS-CoV- -2 is found in different organs, in addition to the lungs and nasal mucosa (intestine, kidneys, liver, muscles), the inflammation was restricted to the lungs, spleen and lymph nodes. “In this way, the lymphocytes were reaching the lungs to perform their functions. It remains to be seen whether those who are arriving are sufficient and whether they are activated efficiently to fight viral infection”, she observes. There are no findings on this yet. “In addition, the presence of lymphocytes, macrophages and neutrophils in the lungs together with the high viral load may be generating intense inflammation that has a deleterious role, destroying the lung tissue, causing the Acute Respiratory Distress Syndrome (ARDS) and respiratory failure. This means that a major challenge for serious forms of COVID-19 is to achieve a balance between the protective response that eliminates the viral load and to prevent this same response from being harmful to the lung tissue, says the researcher.

Regarding immunity to SARS-CoV-2, what is known so far is that after infection, there are people who produce IgM and IgG antibodies, others do not produce antibodies. Regarding the cellular response, there appear to be three immunotypes that were evaluated in peripheral blood samples: i. individuals who have a pattern of T lymphocytes that proliferate a lot, express markers of clonal activation and exhaustion; ii. individuals who have a pattern of T lymphocytes that proliferate less; iii. approximately 20% of individuals who had minimal T lymphocyte activation, with immunotype 1 being identified in the most severe cases.

Another study showed that moderate cases were grouped by low expression of pro-inflammatory cytokines and increased expression of genes related to tissue repair and growth factors. Severe cases were grouped by expression of pro-inflammatory cytokines and type 2 cytokines. “As the severe disease progressed, there was an increase in IFN- aand IFN- ?. Thus, it appears that dysregulation in the cellular response mediated by T lymphocytes is associated with the severity of the disease. Antibodies certainly play a protective role in the initial stage of infection. It remains to be seen whether antibodies can cause an increase in Antibody dependent enhancement (ADE) infection, something that has already been described for other viral infections, such as dengue, for example”, points out Dr. Bonato.

The researcher recognizes that low viral loads can induce an immune response with a more protective profile, without causing the disruption of the response mediated by T lymphocytes and without causing excessive cell death and without causing cytokine storm. “Perhaps with a low viral load, the occurrence of viruses temporarily in the extracellular environment is less, and this results in less recognition by B lymphocytes, and consequently, less production of antibodies. But this differs in saying that it did not produce antibodies”, she points out. She believes that there will always be production of antibodies, perhaps in low concentrations, and the sensitivity of serological tests does not allow detection. Still according to her, it is possible that previous infections with other coronaviruses may induce memory B and T lymphocytes that have the ability to cross-recognize the SARs-CoV-2 antigens.

Asked whether pre-existing T cells can limit the intensity of the infection or even prevent the patient from becoming ill when exposed to the new coronavirus, Professor Bonato admits the possibility. According to her, one way to investigate this would be to study asymptomatic individuals, who would be contacts of patients with COVID-19, and individuals with mild infection, analyzing blood samples and evaluating their T lymphocytes with respect to frequency and functional response. to antigens from different coronaviruses.

Regarding the importance of evaluating cellular immunity in clinical trials with vaccines, Professor Bonato is categorical in saying that it is essential to evaluate the induction of T cell-mediated immunity induced by candidate vaccines. The protection provided predominantly by antibodies should be highly protective if the candidate vaccine induces high titers of neutralizing antibodies, she concludes.

Finally, Professor Dra. Santos also mentions that a Chinese study showed that antibodies in sera of patients with severe symptoms of Middle East respiratory syndrome (SRME or MERS), even though they are neutralizing, promote the production of exuberant patterns of pro-inflammatory cytokines in phagocytic cells, which, as we know so far, they cause severe COVID-19 (the cytokine storm). According to her, the hypothesis investigated to explain this phenomenon is whether the patterns of glycans that line the Fc portion of antibodies in patients with severe COVID-19 differ from the patterns of glycans found in patients with less severe forms. The Fc portion is the portion of the antibody that makes interactions with phagocytic cells, etc., which participate in the effect of the immune response; even though viruses are neutralized by antibodies, they are ingested, along with antibodies, by phagocytic cells. “According to glycan patterns, this Fc portion mediates more or less inflammatory responses. In other words, the antibody may even be neutralizing, but if there is a pattern of glycans in the Fc portion that promotes inflammation, this may be unfavorable to the patient”, she ponders.