T lymphocytes can be defined according to the profile of cytokines they secrete—Th1 responses which drive cell mediated immunity are predominantly composed of interferon γ (INFγ) and interleukin (IL)-2, while Th2 responses include IL-4 and IL-10, which control antibody mediated processes. From: The Decade of Autoimmunity, 1999
October 19, 2020 Annette Plüddemann, Jeffrey K. Aronson On behalf of the Oxford COVID-19 Evidence Service Team Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences University of Oxford Pdf to download Summary
What is the role of T cells and antibodies in immunity? Like B cells, which produce antibodies, T cells are central players in the immune response to viral infection [1]. When the SARS-CoV-2 virus, which causes COVID-19, infects epithelial cells, such as those found in the airways, it replicates inside the cells, using the host cell’s biochemical machinery. This causes the host cell to undergo programmed cell death, releasing molecules called damage-associated molecular patterns (e.g. nucleic acids and oligomers) [2]. These molecules are recognized by macrophages and neighbouring endothelial and epithelial cells, causing them to produce pro-inflammatory cytokines, including chemokines (Box 1); examples include
Monocytes, macrophages, and T cells are then recruited to the site of infection by these chemokines and other cytokines and promote further inflammation. As part of this inflammatory response, the recruited T cells produce interferon-gamma (IFNγ) (see also [40]). Box 1. Definitions of some of the terms used in this article
Several types of T cells are involved in this response. CD4+ T helper (Th) cells interact with CD8+ T cells, which drive the cytotoxic response that kills cells infected with the virus. The CD8+ T cells directly recognize viral peptides presented at the surfaces of infected cells, causing apoptosis (a form of programmed cell death) and preventing the virus from spreading further. Follicular helper T (TFH) cells are a specialized subset of CD4+ T cells that provide help to B cells through both cell-cell interactions and release of cytokines, leading to the production of antibodies by B cells [1]. These neutralizing antibodies can recognize whole viruses and act by blocking the virus from infecting cells. Alveolar macrophages recognize the neutralized viruses and the apoptotic cells (killed by the CD8+ T cells) and clear them by phagocytosis. This then results in recovery from the viral infection (Figure 1, adapted from [2]).
Figure 1. Role of T cells in response to COVID-19 infection: adapted from The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020 Jun;20(6):363-374. doi: 10.1038/s41577-020-0311-8. What do we know about T cell responses and antibody production in patients with COVID-19? For many primary virus infections, it typically takes 7 to 10 days to prime and expand adaptive T cell immune responses to control the virus, and this correlates with the typical time it takes for patients with COVID-19 either to recover or to develop severe illness [11]. This raises the possibility that a poor initial T cell response contributes to persistence and severity of SARS-CoV-2, whereas early strong T cell responses may be protective. Lymphopenia Depletion of CD4+ T cells, CD8+ T cells, and B cells, among other immune cells, reportedly occurs [13,14]. Although there is so far limited understanding of the mechanisms of lymphopenia in COVID-19, many patients with severe disease have reduced T cell numbers in particular, and perhaps specifically CD8+ T cells [12], but it is unclear why this is so. Lymphopenia has been reported in infections with other respiratory viruses, such as influenza [15], but seems to last longer in COVID-19 and may be more severe [14]. The CD4+ T cell response in COVID-19 Overall, the CD4+ T cell response in acute SARS-CoV-2 infection, whether impaired, over-activated, or inappropriate, and how this relates to disease outcomes, remains to be elucidated and is an important question. A particularly high frequency of CD4+ T cell responses specific to virus spike protein has been observed in patients who have recovered from COVID-19, which is similar to what has been reported for influenza virus infections [11]. In one small study of 14 patients, circulating virus-specific CD4+ T cells were identified in all of those who recovered from SARS- CoV-2, which also suggests the potential for developing T cell memory [18] and perhaps longer-term immunity. The CD8+ T cell response in COVID-19 It is still unclear how the heterogeneity of the CD8+ T cell response relates to disease features, which could be driven by, for example, patient immunotypes [17,19] or the nature of the interaction between respiratory epithelial cells and cytotoxic T cells and the level of response. Several chemokine receptor genes (including CCR9, CXCR6, and XCR1) and the locus controlling the ABO blood type have been identified as being associated with severe disease; however, whether these genes are directly or indirectly related to T cell responses in COVID-19 remains unknown [14]. A higher proportion of CD8+ T cell responses was observed in patients who only developed mild disease, suggesting a potential protective role of CD8+ T cell responses [11]. Most of the CD8+ T cell responses were specific to viral internal proteins, rather than spike proteins, which should be considered in vaccine development [4]. SARS-CoV-2-specific CD8+ T cells are present in about 70% of patients who have recovered [18], which is evidence of a virus-specific CD8+ T cell response and the presence of CD8+ T cell memory. However, the ability of these cells to protect from future infection remains to be determined. Potential for cross-reactive immunity Potential for long-term immunity SARS-CoV-2-specific memory T cells have also been detected in exposed seronegative healthy individuals (relatives of confirmed cases), which may indicate asymptomatic infection. One study has shown that ~93% of “exposed asymptomatic” individuals had a T cell response to SARS-CoV-2, despite seropositivity in only 60% of cases [28]. Asymptomatic infections may therefore be more common, and antibody testing alone may underestimate the true prevalence of the infection or population immunity. SARS-CoV-2-specific T cells were found in most of the convalescent patients in this study, which is a promising sign that infection may give rise to immunity [29] Potential therapeutic interventions Questions remain around the use of immune checkpoint inhibitors, for example, in cancer therapy, and their role in COVID-19 infection. An example of these are inhibitors of programmed death-1/ligand-1 (PD-1/PD-L1) (e.g. nivolumab and pembrolizumab). COVID-19 may cause T-cell exhaustion with increased expression of PD-1 and PD-L1, and the effect of blockade of these critical pathways is unknown. It could theoretically either mitigate or exacerbate COVID-19 severity [37], depending on the stage of the disease. Trials are required to evaluate these interventions in COVID-19; one trial evaluating pembrolizumab as part of a study assessing checkpoint blockade interventions in COVID-19 is currently underway [38] and several trials are registered planning to assess nivolumab safety and efficacy in patients with COVID-19 [39]. In one study of the effect of PD-1 blockade on the severity of COVID-19 in patients with lung cancers, PD-1 blockade did not appear to affect the severity of COVID-19 in patients with lung cancers [40]. References
Acknowledgements: The authors would like to thank Dr. T. Griseri for helpful discussions. Disclaimer: This article has not been peer-reviewed; it should not replace individual clinical judgement, and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice. |