12/20/21, 11:10 AM A Regenerative Perspective on Successful and Failed T-Cell Immunity

Cold Spring Harbor Perspectives in Biology

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Published in Advance
February 8, 2021,
doi:
10.1101/cshperspect.a037937
Cold Spring Harb. Perspect. Biol.
2021.
13:
Copyright © 2021 Cold Spring Harbor Laboratory Press; all rights reserved

A Regenerative Perspective on Successful and Failed T-Cell Immunity

Steven L. Reiner

+ Author Affiliations

Correspondence: sr2978@cumc.columbia.edu

Abstract

Heightened immunity after a primary infection, persistent control of low-level infection, or vanquished immunity from chronic-active
infection and cancer
are interrelated issues concerning the nature of T-cell regeneration during immunity. For many regenerating
tissues and cellular systems, such as epithelia
and blood, there are at least three distinguishable stages of development
and repair, marked by progressive loss of self-renewal and progressive
commitment to differentiation. T cells seem to be no
different. Quiescent precursors become activated and yield anabolic, proliferative progenitors while
self-renewing the quiescent
precursor population. Activated progenitors then yield differentiated cellular descendants alongside the self-renewal of
progenitors.
Nomenclature reflecting the mutually opposing nature of T-cell self-renewal and T-cell differentiation would help synchronize
phenomena
such as T-cell memory, protective immunity, and T-cell exhaustion with other regenerative paradigms, as well as
offer new strategies to influence the
intensity and duration of immunity.

A major focus in the study of immunological memory is protective immunity, the way in which T cells that eliminated acute
infection (or expanded following
vaccination) can defend the host faster and better upon rechallenge (Jameson and Masopust 2018). Against opportunistic pathogens, selected T cells and
their descendants maintain tight control for decades without undergoing
depletion. In chronic-active viral infection and cancer, initial T-cell responses
often give way to failure, termed T-cell
exhaustion (Blank et al. 2019). Recent progress concerning the nature of these distinct scenarios has revealed a
surprising interrelatedness. The convergent
principle underlying elimination of infection, active long-term pathogen suppression, or failed control by T cells
is the
success or limitations of T-cell regeneration. This review will offer a unifying model and nomenclature for the gamut of T-cell
responses,
emphasizing the critical role for regeneration, that is, maintaining self-renewal alongside differentiation.

ADAPTIVE IMMUNITY IS LAYERED DESPITE BEING IN SOLUTION

When microbial components breach our barrier surfaces, inward antigen drainage (and signaling of pathogen-associated molecular
patterns) become a
representation of the infection within a secondary lymphoid tissue. Upon specific T-cell activation and
differentiation, an outward dispatch of the T cell's
descendants from draining lymph node to the site of infection occurs
in reaction to the breach. To permanently preserve the capacity to defend against the
pathogen, duplicates of the selected
T-cell clone remain in the “central” secondary lymphoid circulation. To become even more battle-ready, duplicates of
the selected
T-cell clone with even greater firepower are stored in more strategic front-line locations.

Perhaps because pathogens are not always eliminated, the cellular network that is spawned from a single T-cell clone stratifies
into an orderly anatomic and
regenerative hierarchy, with similarities to the regeneration of epithelial barriers and blood
cells (Beumer and Clevers 2016; Nish et al. 2017a). Despite the
heterogeneity of immune responses with regard to location of infection, class of pathogen, degree of T-cell
activation, clonal expansion, regeneration,
recirculation, migration, and chronicity, there is a seemingly invariant order,
which, like other regenerative paradigms, could be thought of as containing at
least three “layers”: precursor cells, progenitor
cells, and differentiated cells (Fig. 1). A quiescent “layer,” originally named central memory cells, acts as an
expanded and perhaps more battle-ready population
of replacements for the original naive clone (Sallusto et al. 1999). Like the naive precursor, central
memory cell descendants are also precursors, occupying the aptly named “central” information
hub of immunity. Central memory cells and naive cells
recirculate from T-cell zone to T-cell zone of the secondary (and possibly
tertiary) lymphoid tissue network. The consumption of a naive cell and its
replacement by central memory cells may or may
not be sufficient to mediate protective immunity to a rechallenge, but it should be sufficient to leave the
host as immunocompetent
as it was before the first challenge.

Figure 1.
PDF
Classification of T-cell subsets from a regenerative perspective. This hypothetical, three-layered schema Help
is composed of two
major cell fates and an unstable intermediate state: precursors, progenitors, and
irreversibly differentiated cells. Progressive
commitment to differentiation is accompanied by loss of
self-renewal and multipotency, resembling epithelial or hematopoietic
growth and repair. Activation of
quiescent TCF1+ precursor (red) leads to mobilization of rapidly dividing, anabolic TCF1+ progenitors
View larger version:
In this page
In a new window (purple), while simultaneously self-renewing (looped-back arrows) quiescent descendants (central
Download as PowerPoint Slide memory). TCF1+ progenitors undergoing further activation directly yield irreversibly committed TCF1−
effector blasts (blue, and also anabolic), while simultaneously self-renewing bipotent TCF1+ progenitors.
After antigen clearance, activated TCF1+ progenitors can revert from their unstable anabolic state to
become quiescent TCF1+ precursors, but TCF1− cells do not dedifferentiate into TCF1+ cells. Anatomically, precursors circulate among
secondary lymphoid organs (SLOs), progenitors concentrate in draining lymphoid
organs, and differentiated cells (which arise in draining SLOs)
are subsequently dispatched to tissue sites. Other TCF1− cells emerging from anabolic effector blasts include postmitotic effector and exhausted
cells. TCF1− effector memory and tissue-resident memory cells are hypothesized to arise from progenitors (or effector blasts) and stabilize
into
more quiescent peripheral cells after antigen clearance. During chronic responses, TCF1+ progenitors maintain production of TCF1− descendants

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until capacity for TCF1+ self-renewal is lost. PD-1 blockade hypermobilizes TCF1+ progenitors into greater division and production of fresh
TCF1− progeny, rather than restoring functionality to preexisting exhausted TCF1− cells (not shown).

Naive and central memory cells express substantial levels of the transcription factor TCF1 (Fig. 1), which has become a convenient and increasingly
appreciated marker for the ability of a previously activated T cell to self-renew,
that is, to remake its TCF1+ self while producing TCF1− progeny (Zhou et al.
2010; Lin et al. 2015, 2016; Im et al. 2016; Utzschneider et al. 2016; Nish et al. 2017b; Kratchmarov et al. 2018; Chen et al. 2019; Hudson et al. 2019;
Kurtulus et al. 2019; Miller et al. 2019; Siddiqui et al. 2019; Zander et al. 2019). Although both naive and central memory cells are relatively quiescent, an
important difference between naive and central
memory CD8+ T cells is the ability of the latter to undergo slow or periodic antigen-independent
homeostatic divisions (Jameson and Masopust 2018). It is not clear whether CD4+ central memory T cells divide homeostatically.

SPECIFICATION AND DETERMINATION

Upon activation, naive and central memory T cells must divide and produce differentiated progeny. The most activated initial
cellular descendants are also
TCF1+ and could be considered as the immediate progenitors of effector blasts (Fig. 1). A critical characteristic of this antigen-driven TCF1+ progenitor
population is that it is highly active metabolically (Fig. 1), in contrast to the daughter cells of a homeostatic division, which remain relatively quiescent. In
addition, those most
activated initial TCF1+ daughter cells express substantial levels of many genes associated with effector cells, such as T-bet and IFN-γ,
and while
they are still activated they express low levels of CD62L and CD127 (Lin et al. 2015, 2016). The facultative down-regulation of CD62L may be
important for concentrating progenitors in the most relevant (draining)
lymph node where they were initially activated, rather than freely circulating from
node to node, like the more quiescent
precursors (Nish et al. 2017b).

The TCF1+ progenitors may well be capable of exerting effector function, yet they can be distinguished from the majority population
of bona fide effector
cells because the latter have undergone silencing of TCF1 expression and will concentrate in the relevant
peripheral tissues, rather than remaining primarily
bound to the draining lymph node (Lin et al. 2015, 2016; Nish et al. 2017b). The silencing of TCF1 is stabilized by epigenetic changes at the Tcf7 locus,
which encodes the TCF1 protein (Pauken et al. 2016; Sen et al. 2016; Ghoneim et al. 2017; Gray et al. 2017; Philip et al. 2017). During acute infection, the
nascent TCF1− descendants that arise from TCF1-expressing progenitors are already incapable of reexpressing TCF1 or producing TCF1+ descendants in
their subsequent cell divisions in vivo (Fig. 1). By contrast, the TCF1+ progenitor cells continue to produce TCF1− progeny while self-renewing their TCF1+
selves (Lin et al. 2015, 2016; Nish et al. 2017b).

A key feature of TCF1-expressing progenitors bears relevance to the issues of nomenclature as well as controversies regarding
the ontogeny of memory
cells. After resolution of acute infection and clearance of antigen, the formerly anabolic and activated
TCF1-expressing progenitors appear to revert to
quiescent central memory phenotype cells, including reexpression of CD62L
and CD127, which likely facilitates their reentry into the precursor circulation
of secondary lymphoid T-cell zones (Lin et al. 2016). In contrast, the descendants of the TCF1− progeny fail to contribute to the central memory pool
following clonal contraction (Lin et al. 2016). In view of the finding that activated TCF1-expressing progenitors produce irreversibly determined TCF1−
progeny during antigen activation, but also revert to central memory cells after antigen is cleared, it might be appropriate
to invoke a common paradigm for
progressive lineage commitment, specification (a reversible stage) followed by determination
(an irreversible stage) (Fig. 1).

The reversible distinction between precursor and progenitor (both TCF1+) hinges on the facultative activation state, while the irreversible demarcation
between TCF1+ progenitors and TCF1− descendants is more aptly considered a change in fate, as both the difference in TCF1 status and whether they can
any longer
produce a TCF1+ descendant (and repopulate the niche of central memory cells) transcends their activation state (Lin et al. 2016). Because the
earliest TCF1− effector blasts, while still KLRG1-low and still capable of brisk division, are not seemingly capable of becoming central
memory cells, the
idea that most memory cells dedifferentiate from effector cells could be misleading (Lin et al. 2016; Delpoux et al. 2017; Youngblood et al. 2017). Activated
TCF1-expressing progenitors may look and perform like effector cells but their ability to quiesce and regain
central memory phenotype and localization is
not the same as TCF1− cells regaining TCF1 expression, which, as yet, does not seem to occur under physiologic conditions (Im et al. 2016; Lin et al. 2016;
Utzschneider et al. 2016, 2018; Miller et al. 2019).

It would seem that a potential nomenclature scheme that splits T cells into activation/metabolic status, self-renewal/TCF1-expression
status, and anatomic
location could help to sort most of the major subsets (Fig. 1). TCF1+ progenitors constitute a hybrid and perhaps unstable state. They self-renew like a
stem cell or precursor, but are facultatively
anabolic and effector-like. The term progenitor (of effector blasts, postmitotic effectors, and exhausted cells, as
well as
effector and resident memory cells) has connotations of being the direct producer of an irreversible TCF1− fate as well as still having the stem-like
capacity to self-renew. Unlike the terms “effector” or “memory precursors” for
the highly active TCF1+ cells, “progenitor” better serves to designate their
important role in amplifying effector production by self-renewing, as
well as their unique plasticity to revert to precursors, which their TCF1− descendants
lack.

HETEROGENEITY AMONG DIFFERENTIATED LINEAGES PDF

Nascent KLRG1-low TCF1− effector blasts appear in the first few days following infection, but they are not immediately postmitotic (Lin et al. 2015, 2016;
Help

Delpoux et al. 2017; Nish et al. 2017b). Instead, as they divide they continue to mature into postmitotic, KLRG1-high T cells in the acute phase of infection
(Lin et al. 2016). Among memory cells, effector and tissue-resident memory cells represent more differentiated fates than central memory cells.
Effector
and tissue-resident memory cells tend to remain in their circulating blood and tissue-bound niches, respectively,
beyond the central information hub
occupied by naive and central memory cells. Like nascent TCF1− effector blasts, effector memory and tissue-resident memory cells may retain proliferative
potential upon reactivation (Sallusto et al. 1999; Beura et al. 2018; Kratchmarov et al. 2018; Park et al. 2018).

Although this issue needs to be more fully addressed experimentally, it is tempting to speculate that after antigen clearance
the majority of quiescent
effector memory and tissue-resident memory cells are TCF1− and that their subsequent proliferation after rechallenge is akin to nascent TCF1− effector
blasts; that is, they have not yet reached their mitotic limits (Fig. 1). This model would be consistent with the observation that tissue-resident memory cells
arise from a KLRG1-low cell, rather
than a fully mature, postmitotic, KLRG1-high effector cell. A TCF1−, but not yet postmitotic model of effector and
tissue-resident memory cells would also be consistent with the observation
that TCF1 positively regulates secondary lymphoid homing molecules including
CCR7 and CD62L (Zhou et al. 2010). Alternatively, or in addition, secondary proliferation of tissue-resident memory cells could arise from a subset of
TCF1+ cells that reside in a tertiary lymphoid niche within the tissue (Jansen et al. 2019). In addition to in situ proliferation, some replenishment of tissue-

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resident cells upon rechallenge is likely to be derived
from a circulating source (Beura et al. 2018; Park et al. 2018). The dynamics of T-cell repopulation
within tissues, both normal and cancerous, will therefore require further investigation.

TCF1 MARKS SELF-RENEWING T CELLS ACROSS THE SPECTRUM OF IMMUNITY

In low-level persistent infections that are asymptomatic in immunocompetent hosts, chronic-active infections, and cancer,
the persistence of antigen
demands ongoing regeneration of selected clones. Not surprisingly, the same type of three-layered
regenerative hierarchy (precursor, progenitor, and
differentiated cells) has emerged as a universal feature of the gamut of
T-cell responses, in both preclinical and human patient studies (Chu et al. 2016; Im
et al. 2016; Utzschneider et al. 2016, 2018; Wu et al. 2016; Delpoux et al. 2018; Chen et al. 2019; Hudson et al. 2019; Jansen et al. 2019; Kurtulus et al.
2019; Miller et al. 2019; Siddiqui et al. 2019; Zander et al. 2019). In each case, the self-renewing progenitor of more differentiated cells appears to be
marked and maintained by the expression
of TCF1. In some contexts, the TCF1+ progenitor coexpresses markers associated with T follicular helper cells
and germinal center B cells. Importantly, in each
case, TCF1− cells do not appear to dedifferentiate into TCF1+ cells, whereas TCF1+ cells give rise to TCF1−
cells while self-renewing their TCF1+ selves (Im et al. 2016; Lin et al. 2016; Utzschneider et al. 2016, 2018; Miller et al. 2019).

Unlike acute infections, wherein antigen clearance leads to the consolidation (through quiescence) of TCF1+ progenitors into the TCF1+ precursor pool (Lin
et al. 2016), control of persistent infections requires steady-state maintenance of all three layers: precursors, progenitors, and irreversibly
differentiated
cells. The suppressed replication of opportunistic infections in immunocompetent hosts is dependent on central
memory cells (precursors) periodically
minting fresh, activated progenitors, which in-turn produce fresh, differentiated descendants
(Chu et al. 2016; Delpoux et al. 2018). This raises an
important and sometimes misunderstood issue. T-cell memory is frequently equated with, but not truly the
same as, protective immunity and how antigen-
experienced T cells that persist in unique niches after antigen clearance can
provide faster and better responses to rechallenge.

In the case of pathogen persistence, the three layers are dynamically cooperating to maintain a steady stream of function
that ensures lifelong, low-level
burdens of pathogens that are never eliminated. Such scenarios are reliant on T-cell memory
and regeneration but are distinct from protective immunity. By
contrast, faster and better secondary responses are enabled
by a combination of the longevity and retained proliferative capacity of differentiated effector
and tissue-resident memory
cells, as well as the markedly expanded precursor (central memory) pool that arose after quiescence of the surviving primary
progenitors. Thus, immune memory has multiple meanings and mechanisms, from avoiding the depletion of critical precursors
that are the foundation of
lifelong active responses through the protective immunity achieved by having enhanced numbers of
diverse memory cells positioned in strategic locations
including barriers, blood, and lymph nodes (Jameson and Masopust 2018).

What the field means by “durability” of T-cell memory is also different for acute versus persistent challenges. For persistent
infections, durability is most
importantly manifested by regeneration, the ability of precursors and progenitors to replenish
themselves as they produce their more differentiated
descendants. After acute infection, the homeostatic maintenance or longevity
of poised memory populations (both TCF1+ and TCF1−) becomes as
important as the ability of TCF1+ cells to yield differentiation alongside self-renewal.

SIGNALING LOGIC OF A THREE-LAYERED REGENERATIVE SCHEMA

After T-cell activation during an immune response, the commands for proliferation, differentiation, and migration are set
in motion. To form a successful
and orderly regenerative framework, however, some punctuation or constraints on the signaling
must exist to prevent a precursor from simply giving rise to
a homogeneous set of fully differentiated, peripherally dispatched
descendants. In the initial T-cell divisions, there appears to be signaling heterogeneity,
with one daughter being less metabolically
active than the other (Lin et al. 2015, 2016; Pollizzi et al. 2016; Verbist et al. 2016; Nish et al. 2017b). This
asymmetric anabolic induction results from a hub or cluster of activating receptors formed at the microtubule organizing
center (Chen et al. 2018). That
activating hub remains polarized to one side of the mitotic spindle during cell division (Chen et al. 2018). The resultant sibling cells exhibit unequal
intensity of phosphoinositide 3-kinase (PI3K) signaling, which initially manifests
as a more actively dividing daughter cell (progenitor) and a more quiescent
sibling cell (self-renewal of precursor) (Lin et al. 2015, 2016). Both initial daughter cells are TCF1+. The more quiescent daughter cells (precursors) from the
first divisions remain in secondary lymphoid recirculation and can
soon be found in nondraining lymph nodes (Nish et al. 2017b). The more activated
daughter cells (progenitors), by contrast, concentrate in the draining secondary lymphoid tissue (Nish et al. 2017b).

When the progenitor undergoes further antigenic stimulation and divisions, it too divides asymmetrically, yielding one daughter
cell that inherits more
intense PI3K activity, thereby inactivating the transcription factor FoxO1 and silencing expression
of TCF1 (effector blast, a term conveying
determination/irreversibility of fate but not full maturity) (Lin et al. 2015, 2016; Nish et al. 2017b; Chen et al. 2018). Coregulated with the loss of TCF1
expression is the liberation of TCF1− cells from the draining lymphoid tissue and the instruction to go to the site of infection (Nish et al. 2017b). The
daughter cell that inherits less PI3K activity maintains activity of FoxO1 and its target TCF1 (the act of progenitor
self-renewal) and is retained in the
draining lymphoid tissue, as if to measure the need for more or less effector production
based on the amount of antigen drainage (Nish et al. 2017b).

From two lopsided cell divisions, the formation of three layers, each with its own anatomic specificity, is apparently demarcated
(Fig. 1). It is yet unclear
PDF
what constraints prevent the more activated daughter of the first division from becoming an immediate
TCF1− effector blast. It is speculated that sufficient
activation energy to repress TCF1 may only be achieved by signaling events
integrated over more than one cell division, for example, progressive assembly Help

of a repressive chromatin structure at the

Tcf7 locus. In most regenerative paradigms, whether stratified into actual layers (epithelia) or in layered-in-
solution (hematopoiesis),
interspersed between the quiescent stem cell–like layer and the differentiated cell layer, usually lies a highly proliferative,
self-
renewing middle layer.

It is important to note that within each of these three layers or bins (quiescent TCF1+, highly active/anabolic TCF1+, and TCF1−) there is further
heterogeneity. For example, the differentiated TCF1− bin contains anabolic/dividing nascent effector blasts as well as postmitotic terminal effector and
exhausted cells during
ongoing responses (Fig. 1). Irreversibly determined, nascent effector blasts arise in draining secondary lymphoid tissues and are
subsequently dispatched
to tissues sites. After antigen clearance, more quiescent, anatomically distinct effector and resident memory TCF1− cells await
rechallenge, when they might again proliferate. The relatively quiescent TCF1+ bin will contain naive and central memory cells that have never, or not
recently, been activated, but will also contain the
more quiescent daughter cells being actively generated during infection. TCF1+ progenitors are likely to
exhibit some heterogeneity of location outside of a canonical secondary lymphoid tissue, within
tumors or perhaps chronically inflamed tissue sites,
possibly owing to a tertiary lymphoid niche (Jansen et al. 2019). TCF1+ progenitors are also likely to exhibit heterogeneity depending on whether they are

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involved in responses to acute infection,
low-level persistent infection, or chronic-active infection and cancer. Finally, TCF1+ progenitors might also exhibit
heterogeneity based on the amount of antigen activation they have undergone.

T-CELL REGENERATIVE FAILURE

Repetitive, high-level antigen activation induces T-cell “exhaustion,” which encompasses at least two separable features that
bear consideration with regard
to a unifying nomenclature. Historically, the predominant connotation of T-cell exhaustion
has been the apparent dysfunction of the most differentiated
TCF1− cells, which are TOX1+ and marked by highest-level Tim3 and PD-1 coexpression (Blank et al. 2019). Separately, T-cell responses against chronic-
active viral infections and cancer can eventually erode owing to regenerative
failure. A variety of preclinical and patient studies suggest that high-level
antigen activation depletes self-renewal from
the top of the regenerative hierarchy downward, first with the loss of quiescent precursors, followed by
eventual loss of
active progenitors (Wherry et al. 2004; Blackburn et al. 2008; Paley et al. 2012; Sade-Feldman et al. 2018; Blank et al. 2019; Miller et al.
2019). In addition to the dysfunction of the most terminally differentiated TCF1− cells, T-cell exhaustion is also a regenerative failure, with loss of critical
TCF1+ cell self-renewal.

The insight that maintenance of T-cell populations under the onslaught of high-level antigen activation is a regenerative
problem has also become a focal
point of immunotherapy. Intuitively, it was presumed that interventions like PD-1 blockade
“reinvigorated” exhausted T-cell responses by restoring vigor to
the least vigorous T cells, which express the highest levels
of PD-1. Instead, it was subsequently discovered that PD-1 blockade worked by inducing
enhanced proliferation of PD-1-intermediate
TCF1+ progenitors as well as increasing progenitor production of nascent TCF1− cells (Blackburn et al. 2008;
Paley et al. 2012; Im et al. 2016; Sade-Feldman et al. 2018; Miller et al. 2019). The apparent efficacy of treatment results from the mercurial functionality of
nascent TCF1− cells prior to their transition to postmitotic, terminally exhausted, dysfunctional cells (Chen et al. 2019; Hudson et al. 2019).

CONCLUDING REMARKS

T-cell regeneration, which is key for durability in chronic immune responses, is a balancing act of differentiation and self-renewal.
Presumably owing to the
high-level antigen activation, failing T-cell responses in chronic-active processes show signs of
imbalance toward greater differentiation and loss of self-
renewal (Paley et al. 2012; Blank et al. 2019). Unleashing activation, proliferation, and differentiation of progenitors using PD-1 blockade has the potential
to further
tip the balance toward differentiation over renewal (Im et al. 2016; Sade-Feldman et al. 2018; Chen et al. 2019; Miller et al. 2019). It is possible
that future application of immunotherapies against cancer will require assessment of the T-cell regenerative
status to tailor individualized treatment (Sade-
Feldman et al. 2018; Jansen et al. 2019). A challenge for T-cell memory as it concerns protective immunity, vaccination, as well as cancer immunotherapy is
how to
better harness the dispatch and replenishment of tissue-resident cells during homeostasis and active immune reactions. A unifying
model and
nomenclature for the dynamic adaptability of T-cell regeneration across diverse circumstances will only help accelerate
our understanding and utilization of
its promise.

ACKNOWLEDGMENTS

I dedicate this to the memory of my parents, Julius and Sophie, whose encouragement never faltered.

Footnotes

Editors: David Masopust and Rafi Ahmed

Additional Perspectives on T-Cell Memory available at www.cshperspectives.org

Copyright © 2021 Cold Spring Harbor Laboratory Press; all rights reserved

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