Dysfunctional T cells present at high levels in severe COVID-19

The current outbreak of COVID-19 is taking a heavy toll on human health, social interaction, and economic activity, with over 12.87 million cases and over 568,000 deaths. However, the severity of the disease varies from patient to patient.

Now, a new study by researchers at Saarland University, Germany, and published on the preprint server medRxiv* in July 2020 shows that there are higher levels of anti-SARS-CoV-2 T cells, which show significant alterations in the phenotype and function.

3d illustration of immune system T cells attacking cancer cells. Image Credit: Meletios Verras / Shutterstock
3d illustration of immune system T cells attacking cancer cells. Image Credit: Meletios Verras / Shutterstock

Earlier research shows that the virus causes broad changes in cellular immune response, seen chiefly as lymphopenia, alteration in the proportion of different T cell subpopulations, and increased plasma cytokines within inflammatory pathways. The T cells themselves show altered function, reflected in the reduced production of interferon-gamma (IFNγ). The current study aims at evaluating specific T cell immunity targeting the virus, which has been little studied so far, especially concerning the diverse spectrum of disease severity.

As is typical with other viral infections, SARS-CoV-2 infection should follow different courses depending on the strength of the immune response, both humoral and cellular. Patients with this infection seroconvert normally, with both IgM and IgA antibodies being induced early (median 5 days), and IgG at a median of 14 days. Earlier, the researchers demonstrated changes in the count and functionality of T cells targeting the specific pathogen in persistent symptomatic infections relative to those who overcome the infection.

Therefore, they aimed at testing whether the T cells in COVID-19 also undergo similar changes in severe disease compared to mild. Secondly, they attempted to explore the occurrence of alterations in B cell types and in SARS-CoV-2 specific antibodies in response to the T cell phenotypes targeting specific antigens.

The Study: Relating T Cell Phenotype to Disease Severity

The study included 50 patients, all with symptom onset at 42.5 days before the study began. There were 14 critically ill patients in the intensive care unit (ICU) and 36 who had recovered without severe illness.

Expectedly, ICU patients were older compared to the other group. Ten and seven of them had cardiovascular and metabolic diseases, respectively. The median time to admission from the earliest symptom was 5 days and to ICU admission 7 days. Of the 14, 11 required mechanical ventilation, 7 of the 11 also required extracorporeal membrane oxygenation and 7 treatment for renal failure. Three patients died within 2 weeks of the study date. Of the 14, 12 returned negative tests for the virus on PCR during hospitalization, but 33/36 in the convalescent group.

Total and Lymphocyte Counts Altered in Severe COVID-19

The total leukocyte count was different between ICU and convalescent patients, the most apparent alteration being higher neutrophil levels and very low lymphocyte counts in the former. Differential white cell counts showed that all lymphocyte subpopulations were reduced, including NK, B and T cells of both CD4 and CD8 lineages, and regulatory T (Treg) cells.

T Cells in Severe COVID-19

Stimulation with major SARS-CoV-2 antigens identified specific T cells targeting this virus. The highest responses were in the CD4 T cell subpopulation towards the spike N-terminal antigen and viral membrane protein VME1, and then spike C-terminal antigen and the nucleocapsid NCAP protein. CD8 T cells were less frequent and reacted mostly to spike-N and NCAP.

Higher CD4 T cell counts were found in patients (ICU and convalescent) compared to controls, and CD8 T cells were also more frequently specific for spike-N or CAP. Recovered patients who had symptoms of lower respiratory tract involvement had double the frequencies of CD4 T cells compared to individuals without them.

The overall frequencies of specific CD4 T cells were highest in severe COVID-19, but nonspecific CD4 T cells were lowest in this group. Specific CD8 T cells rose in patients in both groups, but not the nonspecific cells. Another difference between CD4 and CD8 T cells was in the time frame. The latter showed a fall as the duration since symptom onset increased, but not the former. Thus, overall the researchers concluded that patients with severe COVID-19 had high specific T cell frequencies.

Cytokine functionality of T cells in Severe COVID-19

The proportion of specific T cells producing all three cytokines IFNγ, IL-2, and TNFα were significantly lower in patients with severe disease than in the convalescent group, while cells producing two, namely, IL-2 and TNFα, was higher.

Polyclonal and specific T cells had different cytokine profiles, but both also showed differences in the convalescent and ICU groups. Polyclonal CD4 T cells in convalescents and controls showed a similar cytokine expression.

This means that in severe disease, cytokine expression is restricted for both specific and polyclonal T cells. When specific CD4 T cells expressing CTLA-4 were measured, they were higher in ICU than in convalescent patients. The trend was similar for polyclonal CD8 T cells, though in fewer patients.

T Cell Phenotype in Severe COVID-19

Both CD4 and CD8 T cells expressed CTLA4 and PD1 at higher levels in ICU patients than in controls or convalescents. Recently proliferated CD4 and CD8 T cells with Ki67 expression were higher in ICU patients than in the other groups.

CD4 T Cells and Specific Antibodies

Both specific IgA and IgG were positive in severe COVID-19 patients, and at higher levels than in convalescent patients. In the latter group, 83% and 69% had detectable IgG and IgA. Specific antibodies were correlated with specific CD4 T cells, but not with specific CD8 T cells.

B cells were in general lower among severe COVID-19 patients, including naïve and memory cells (both those which had switched and those which had not). The plasmablast count (switched CD38 B cells) were higher, however, in this group. Thus, these cells play a crucial role in antibody production.

Implications and Future Directions

The specific immunity in severe disease is thus clearly different from that in convalescents. The study suggests that measuring CD4 T cells specific for the virus may allow differentiation of severely and mildly ill patients as well as those who are infected vs. the uninfected.

Secondly, it suggests, “Patients with severe course may have required induction of higher levels of specific immunity due to higher viral load or prolonged periods of active viral replication.”

This could be due to the seeding of the virus in the lung in severe disease, vs. restriction to the upper airway in mild disease. The former may be promoted by a high viral load in the nose and throat, along with advancing age, diabetes, or obesity, all of which promote the aspiration of microscopic amounts of the virus. This may be why the former needs lower levels of specific immunity. Preexisting cross-reacting antibodies may also modulate this.

Thirdly, lower expression of CTLA-4 may correlate with better viral control, and higher expression with persistent and more severe infection. The limited cytokine spectrum of the specific T cells bears out the hypothesis of the primary induction of immunity. In reactivation, on the other hand, as cells shift toward exclusive IFNγ expression, there is a loss of multifunctional cells. This does not agree with the exhaustion of T cells, despite several common characteristics, because of the strong T cell response seen with high proliferative potential.

Instead, it may be, the researchers suggest, “physiological contraction mechanism to downregulate specific immunity after its strong induction and to compensate for excessive immunopathology in the lung.”

Finally, the high plasmablast and antibody levels may correlate to neutralization capacity and viral clearance.

However, the paper concludes, “Further studies should address whether antibodies may also contribute antibody-dependent enhancement of viral entry into Fc-receptor expressing cells such as macrophages thereby leading to increased inflammation and lung injury.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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