key: cord-0908712-lnwpax2p
authors: Jarjour, Nicholas N.; Masopust, David; Jameson, Stephen C.
title: T cell memory: Understanding COVID-19
date: 2020-12-19
journal: Immunity
DOI: 10.1016/j.immuni.2020.12.009
sha: 9dd36480744b0c6b77d6877821e2acc666af12c1
doc_id: 908712
cord_uid: lnwpax2p

As the SARS-CoV-2 pandemic has progressed, increasing attention has focused on establishing natural and vaccine-induced immunity against this coronavirus and the disease, COVID-19, that it causes. In this Primer, we explain the fundamental features of T cell memory and their potential relevance for effective immunity to SARS-CoV-2.

As the SARS-CoV-2 pandemic has progressed, increasing attention has focused on 22 establishing natural and vaccine-induced immunity against this coronavirus and the disease, 23 COVID-19, that it causes. In this Primer, we explain the fundamental features of T cell memory 24

and their potential relevance for effective immunity to SARS-CoV-2. This leads to T cell differentiation into a range of effector cell types tailored to control the 32 invading organism (Table 1) . Different types of pathogens require distinct immune effector cell 33 types to be controlled. In the case of viral infections, these usually include "follicular helper" 34 CD4 + T (Tfh) cells that induce B cells to produce high affinity antibodies capable of neutralizing 35 the pathogen, and cytolytic CD8 + T cells that kill pathogen-infected cells. Clonal diversity in the 36 pre-immune "naïve" T cell population means rare cells will be present with TCRs able to 37 recognize a new pathogen, such as SARS-CoV-2. In a productive immune response, these 38 specific T cell populations undergo dramatic numerical increases and differentiate to manifest 39 appropriate effector functions for elimination of the pathogen. This is usually followed by a 40 substantial loss of effector cells but preservation of an elevated number of durable "memory" T 41 cells of various types, also termed subsets (Table 1) , which can be efficiently deployed if an 42 individual is reinfected by the same pathogen ( Figure 1A ). Since effective immune memory can 43 persist for decades and typically results in enhanced responses and accelerated pathogen 44 J o u r n a l P r e -p r o o f memory progenitor cells to deal with potential future reinfections. These signals include soluble 71 factors such as cytokines and cell-cell interactions, including with dendritic cells presenting 72 pathogen-derived antigens and costimulatory/inhibitory ligands to naïve T cells, as well as CD4 + 73 T cell help to CD8 + T cells. If any of these requirements are not met appropriately, the primary 74 response may be ineffective or overblown, resulting in pathology in the host and/or impaired 75 development of memory. In the case of ineffective priming or generation of "exhausted" T cells 76 that progressively lose effector potential due to an unresolved, chronic infection ( Figure 1B) , 77 these T cell populations are likely to either be lost over time or enter a permanently 78 dysfunctional state, even if the host survives. At the other extreme, T cell responses may 79 become dangerously exuberant, leading to excessive tissue damage and/or a life-threatening 80 cytokine storm, collectively termed immunopathology ( Figure 1C ). This can lead to persistent, 81 systemic changes in the immune system altering future immune responses, including the 82 development of memory cells and their response to rechallenge with the offending pathogen. 83

One final possibility we will consider is that an individual's microbial experience may mean they 84 don't start with an immunologically "clean slate" -for example, memory T cells generated in 85 response to one pathogen may cross-react with another with highly similar antigens, such that 86 the response to a "new" pathogen involves reactivation of pre-existing memory T cells ( Figure 2 ) 87 and thus differs from the other scenarios. This can result in a variety of outcomes, including 88 enhanced control as compared to a de novo naïve response, as will be discussed further. 89

There is emerging evidence that all these modes of memory T cell generation and response A protective primary T cell response against a viral pathogen requires recruitment and activation 96 of antigen-specific naïve CD4 + and CD8 + T cells, rapid population expansion, and differentiation 97 into suitable effector cell types to mediate an appropriate immune response. In the case of 98 SARS-CoV-2, CD4 + and CD8 + T cells producing interferon (IFN)-γ (commonly referred to as a 99 However, two scenarios reinforce the relevance of effective T cell memory. First, 138

inadequate generation or persistence of neutralizing antibodies could limit the efficacy and 139 longevity of serological immunity against SARS-CoV-2 infection or vaccination. This is not just a 140 hypothetical concern -long-term studies of patients who recovered from the closely related 141 influences the response to SARS-CoV-2 infection and/or vaccination in subjects with such pre-212 existing memory T cells is not known, as are any positive or negative consequences for control 213 of the pathogen or generation of neutralizing antibodies. As a high proportion of the world's 214 population will presumably become infected with SARS-CoV-2 or be vaccinated, whether either 215 of these events will alter our responses to other coronaviruses in the future should also be 216 carefully monitored. Hence, the significance of memory T cell cross-reactivity between SARS-217

CoV-2 and other coronaviruses is unclear but will undoubtedly be the topic of considerable 218 investigation. 219

In the human population, the course of COVID-19 disease varies dramatically, ranging from 222 asymptomatic and/or mild infection to life-threatening illness. Early in the pandemic, it became 223 apparent that advanced age is a significant risk factor for severe disease (Moderbacher et al,  224 2020). These aspects of COVID-19 raise concern as to whether the development of immune 225 memory varies depending on the age of the individual or the severity of disease. As discussed 226 earlier, the naïve T cell pool becomes smaller in older individuals, which could conceivably 227 impair responses to novel pathogens, as has been proposed for SARS-CoV-2 (Moderbacher et 228 al, 2020). However, it is still unclear whether T cell memory against SARS-CoV-2 is broadly 229 impaired in the elderly after natural infection or vaccination. As successful vaccination of older 230 individuals is particularly challenging, whether the vaccine candidates currently in development 231

can induce protective immunity, including T cell memory, in the elderly will greatly influence the 232 effectiveness of targeted vaccination of high-risk groups. 233

The development of T cell memory is intimately tied to the dynamics of the immune 234 response. For classical memory to develop, the infectious agent (or at least its protein antigens) 235 must be cleared. When this does not take place during chronic infections (such as HIV), generation of T cell memory in survivors will be important to assess. To this point, T cell 253 immunity at early timepoints after COVID-19 generally appears to be relatively resilient across a 254 spectrum of disease severity. As SARS elicits more severe disease and more durable memory 255 than common cold coronaviruses, whether more severe COVID-19 disease will result in more 256 durable T cell memory is a relevant and important question to address. replicate to high levels, an appropriate T cell response specific to that pathogen (Pink T cells) 329

develops and contributes to control and clearance of the infectious agent. The T cell population 330

is then maintained at a low frequency as a mixture of memory subsets (Table 1) . B cell memory 331

(not shown) is also generated. If the same pathogen later reinfects the individual, memory T 332 cells will rapidly respond and contribute to clearing the pathogen more quickly than during the 333 primary response. However, there are also several less-optimal outcomes. (B) If the immune 334 response cannot clear the infectious agent, a chronic infection will develop. This can cause T 335 cells to enter a so-called exhausted (or hypofunctional) state (represented by lighter-colored T 336 cells) rather than developing classical memory. (C) If the initial response is too strong 337

(represented by dark red T cells), the immune response can cause damaging 338 immunopathology, potentially including a cytokine storm. This can be fatal and survivors may 339 have lasting changes in subsequent immunity (not shown). 

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