COVID-19 is a serious disease. Understanding the immune response is important for effective treatment and prevention. The group of Stanley Perlman (1) did a good job in terms of clarity in their description of the role of T-cell mediated immune response to coronavirus infections. Notably, they focus on the very similar SARS-CoV-1 virus that caused a smaller epidemic in 2002-2004. Below, there is a curated extended citation form a 2014 paper by the Stanley Perlman group (1).
Introduction.
During the 2002–2003 epidemic, SARS-CoV infection resulted in an overall 10 % mortality. While 100 % survival was observed in young (below 24 years old) SARS-CoV infected patients, the mortality rate was above 50% in elderly individuals aged 65 and above [11].
Initiation of the immune response.
Initiation of the immune response against invading pathogens begins with direct infection of airway epithelium. Following initial infection, lung-resident respiratory dendritic cells (rDCs) acquire the invading pathogen or antigens from infected epithelial cells, become activated, process antigen and migrate to the draining (mediastinal and cervical) lymph nodes (DLN). Once in the DLNs, rDCs present the processed antigen in the form of MHC/peptide complex to naı¨ve circulating T cells. Following engagement of the T cell receptor (TCR) with peptide–MHC complex and additional co-stimulatory signals, T cells become activated, proliferate vigorously and migrate to the site of infection 31–33. Once at the site of infection, activated virus-specific effector T cells produce antiviral cytokines (IFN-c, TNF-a, IL-2), chemokines (CXCL-9, 10 and 11) and cytotoxic molecules (perforin and granzyme B) [34]. Effector cytokines such as IFN-c directly inhibit viral replication and enhance antigen presentation [35]. The chemokines produced by activated T cells recruit more innate and adaptive cells to control pathogen burden. Cytotoxic molecules such as granzyme B directly kill infected epithelial cells and help eliminate the pathogen [36–39]. Despite a wealth of information on the T cell response to many respiratory pathogens, less is known about the respiratory coronavirus infections.
Virus-specific T cells and the primary immune response to SARS-CoV in humans.
The acute phase of SARS in human patients was associated with marked leukopenia with severe lymphopenia (80 % of patients), involving a dramatic loss of CD4 T cells (90–100 % of patients) and CD8 T cells (*80–90 % patients) in comparison with healthy control individuals [40–42]. Subsequent studies showed impaired CD4 and CD8 T cell activation in SARS-CoV-infected patients as determined by CD25, CD28 and CD69 expression on CD4 and CD8 T cell subsets [43, 44]. Severe SARS-CoV infection in humans was characterized by the delayed development of the adaptive immune response and prolonged virus clearance [45]. In addition, leukopenia and associated lymphopenia are also observed in MERS patients, albeit to a lesser degree than that observed in SARS patients. A detailed clinical study showed that 14 % of MERS patients were leukopenic, while 34 % of the patients had lymphopenia [46]. Decreased numbers of T cells strongly correlated with the severity of acute phase of SARS disease in humans [42, 47]. Although SARS-CoV is not known to productively infect T cells, altered antigen presenting cell (APC) function and impaired DC migration resulting in reduced priming of T cells likely contribute to fewer number of virus-specific T cells in the lungs [27, 48, 49]. Other possible explanations for T cell lymphopenia include an exuberant type I IFN response and high levels of glucocorticoids resulting from a normal stress response both of which might induce T cell apoptosis [50]. Currently, much less is known about the fate of T cells in MERS-CoV-infected patients.
The effector phase of an immune response is followed by a sharp contraction in the number of antigen-specific T cells, with 90–95 % of virus-specific T cells undergoing apoptosis [89]. The contraction phase is followed by a memory phase in which a stable pool of memory T cells is maintained for a prolonged period of time. Such memory T cells are programmed to counter subsequent infection with the same or related pathogen, mounting rapid responses on reexposure to the pathogen in question, with minimal requirement for co-stimulatory signals [34]. It is well established now that memory T cells are unique in their anatomic distribution, function, maintenance and response to recall [34, 90–92]. Recent advances highlight the key role of virus-specific tissue-resident memory cells in effectively countering a local pathogen challenge. These tissue-resident memory T cells are well equipped to generate a rapid recall response as they are located at the site of infection and possess potent lytic activity and granzyme B expression [93]. The tissue-resident memory T cells secrete cytokines (IFN-c) and chemokines (CXCL9-11) that activate innate cells and attract more memory T cells from the periphery [91, 92]. Following a respiratory tract infection, memory T cells reside both in the lung airways and in lung interstitial tissue. The lung airways contain a high proportion of antigen-specific T cells in comparison with those in the lung interstitial tissue. Conversely, lung-airway-resident memory T cells lack constitutive cytolytic activity and do not proliferate in situ [94]. However, these cells are constantly replenished from the circulation, and recruitment of these cells from circulation depends on CXCR3 expression [95].
Virus-specific memory T cell responses in humans
“Neutralizing Abs and the memory B cells response to SARS-CoV decline significantly after 1–2 years post-infection and are also strain specific.”
Although difficult to address in humans, recent studies highlight the importance of virus-specific T memory cells in patients with respiratory disease. Thus, Sridhar et al. [96] showed that the presence of memory T cells correlated with protection during the recent epidemic caused by the H1N1 strain of influenza A virus. However, most of our understanding of virus-specific memory T cells in the lungs is derived from experimental studies using either influenza or Sendai virus in mice. In terms of patients with SARS, several studies have identified virus-specific memory CD4 and CD8 T cells in patients who recovered from the infection as long as four years after acute infection. In one such study, CD8 T cells specific for HLA-A*02:01-restricted epitopes in the spike protein (SSp-1, S978 and S1202) were identified in surviving patients over one year post-infection. These virus-specific CD8 T cells produced high levels of effector cytokines (IFN-cand TNF-a) and cytotoxic molecules (perforin and granzyme B) after peptide stimulation in vitro [97]. Memory CD4 T cells specific for HLA-DR08- and HLADR15-restricted epitopes within the S protein of SARS-CoV were also identified in recovered individuals [58]. Using pools of overlapping peptides, N, M and E protein-specific CD4 and CD8 T cells were identified in PBMCs from SARS-recovered individuals at 2-years post-infection. Virus-specific CD4 T cells mainly exhibited a central memory phenotype (CD45RA CCR7 ? CD62L -), whereas CD8 memory T cells were effector memory cells (CD45RA ? CCR7 -CD62L -)[53, 55, 98, 99]. In a phase I clinical trial, vaccination of healthy individuals with rDNA encoding spike (S) protein of SARS-CoV elicited both neutralizing antibodies and the spike-protein specific T cell responses. The majority of SARS-CoV spike protein-specific T cells were CD4 T cells (10/10 subjects), and a minority of subjects had detectable spike protein-specific CD8?T cell responses (2/10 subjects) [100]. Collectively, these studies suggest a potential role for virus-specific memory T cells in broad and long-term protection against SARS-CoV infection. This is important as neutralizing Abs and the memory B cells response to SARS-CoV decline significantly after 1–2 years post-infection and are also strain specific.
Selected references:
1. Rudragouda Channappanavar• Jincun Zhao• Stanley Perlman, Immunol Res (2014) 59:118–128.
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