Tissue-resident memory T cells found in lungs of people who had COVID-19 10 months ago

Resident memory T (TRM) cells are T cells (both CD4+ and CD8+) strategically residing in peripheral tissues to control mucosal infections and provide rapid and durable immunity locally against re-infection. The role of TRM cells is to protect against pathogen challenge for many tissues, including the lung and to limit re-infections locally.

Scientists hypothesize that these cells are probably required to limit SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) spread and COVID-19 (coronavirus disease 2019). Because these cells are non-circulating, it is difficult to examine these cells in the blood as they move to the lung parenchyma.

In recent research by Judith Grau-Expósito et al., scientists identify circulating virus-specific T cell responses during acute SARS-CoV-2 infection with functional, migratory, and apoptotic patterns modulated by viral proteins and associated with clinical outcome.

In this study, published in the journal Nature Communications, the researchers found that 1) a balanced anti-inflammatory response is associated with a better outcome in a viral infection, and 2) persisting TRM cells are important for future protection against SARS-CoV-2 infection.

The COVID-19 severity is associated predominantly with IFNγ, and IL-4 responses increased responses against the viral S peptides and apoptosis. However, non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides, and SARS-CoV-2-specific CCR7+ T cells secreting IL-10.

Even 10 months after initial infection, lung-TRM cells are frequently found in convalescent patients, despite the fact that contemporaneous blood does not reflect tissue-resident profiles.

Many questions on the protective immunity post-natural infection are unanswered by the research. It is important to identify specific immunological parameters that can predict disease control – these are the new biomarkers that help in medical decisions. Although neutralizing antibodies play a pivotal role in controlling infections, they diminish over time as has been demonstrated for other coronaviruses. Specific memory T cells are known to persist in SARS-recovered patients for up to 6 years post-infection.

This study looks at the role of TRM cells against SARS-CoV-2 infection. It addresses specific questions related to early control of SARS-CoV-2 infection mediated by cellular immunity and long-term protection: (1) the functional profile of antigen-specific T cells associated with disease control; (2) if apoptosis is involved in disease severity; (3) if antigen-specific T cell responses have the potential to migrate to the lung and eventually become TRM cells.

To this end, the researchers recruited clinically defined groups of patients, during the first wave of SARS-CoV-2 infection (spring 2020) at the Hospital Universitari Vall d'Hebron in Barcelona. The cohort included 46 patients in three groups characterized as individuals who were symptomatic non-hospitalized, individuals who corresponded to mild-hospitalized cases, and the rest who required severe hospitalization. One patient from the severe group succumbed to the disease.

In addition to conducting detailed phenotypic and functional analyses, the research team also assessed TRM cells in convalescent patients' lungs.

They analyzed the plasma and intracellular cytokine levels. The analyses indicated group-based differences: the dominance of IL-4 and IFNγ SARS-CoV-2-specific responses with disease severity and IL-10 to minor disease.

They also observed targeted protein-based differences depending on which T cell profiles are generated. This has clear implications in vaccine design.

Further, the researchers assessed the patterns of chemokine receptors (CCR7 and CXCR3) associated with SARS-CoV-2-infected patients to find out if some specific T cells were migrating to the infected tissues.

The researchers then quantified caspase 3, an apoptotic marker, in both antigen-specific and bystander T cells from the different subsets of the study groups. The observations indicated an increased activation-induced cell death associated with viral replication and disease severity affecting total T cells.

Importantly, the researchers confirmed that Ag-specific TRM responses are present in the lungs of convalescent patients – this highlights the establishment and persistence of lung-resident T cell immunity against SARS-CoV-2 viral infection. They showed that SARS-CoV-2-specific TRM persisted for 10 months after infection.

However, the researchers point out that in most cases, the antigen-specific TRM patterns, both in magnitude and profile, could not be identified in T cells from the blood.

"This study identifies unique features of the cellular immunological response against SARS-CoV-2 relevant to infection control and disease progression, which may be critical to informing vaccine assessment and development of new prototypes."

This study sheds information on the immunological parameters associated with disease control and patient prognosis that will eventually aid vaccine development and monitoring of vaccinated individuals towards the prediction of immune control.

"Our findings encourage next-generation vaccine designs to consider including viral proteins beyond the spike protein, in particular nucleocapsid peptides, which should broaden and balance the functional profile of memory T cells, resembling control of natural infection", the researchers conclude.

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.