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TCR affinity controls the dynamics but not the functional specification of the Th1 response to mycobacteria

26 Oct 2020-bioRxiv (Cold Spring Harbor Laboratory)-

TL;DR: A distinct yet cooperative role for IL-12 and TCR signalling in Th1 differentiation is revealed and it is suggested that the temporal activation of clones with different TCR affinity is a major strategy to coordinate immune surveillance against persistent pathogens.
Abstract: The quality of T cell responses depends on the lymphocytes’ ability to undergo clonal expansion, acquire effector functions and traffic to the site of infection. Although TCR signal strength is thought to dominantly shape the T cell response, by using TCR transgenic CD4+ T cells with different pMHC binding affinity, we reveal that TCR affinity does not control Th1 effector function acquisition nor the functional output of individual effectors following mycobacterial infection. Rather, TCR affinity calibrates the rate of cell division to synchronize the distinct processes of T cell proliferation, differentiation and trafficking. By timing cell division-dependent IL-12R expression, TCR affinity controls when T cells become receptive to Th1-imprinting IL-12 signals, determining the emergence and magnitude of the Th1 effector pool. These findings reveal a distinct yet cooperative role for IL-12 and TCR signalling in Th1 differentiation and suggests that the temporal activation of clones with different TCR affinity is a major strategy to coordinate immune surveillance against persistent pathogens.
Topics: T-cell receptor (65%), T cell (56%), Effector (53%)

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1
TCR affinity controls the dynamics but not the functional specification
1
of the Th1 response to mycobacteria
2
Nayan D Bhattacharyya
1,2
, Claudio Counoupas
3,2
, Lina Daniel
1,2
, Guoliang Zhang
4,1,2
, Stuart J
3
Cook
5
, Taylor A Cootes
1,2
, Sebastian A Stifter
1,2
, David G Bowen
7,8
, James A Triccas
3,2,6
, Patrick
4
Bertolino
7,8
, Warwick J Britton
2
& Carl G Feng
1,2,6*
5
6
Affiliations:
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1
Immunology and Host Defense Group, Department of Infectious Diseases and Immunology,
8
School of Medical Sciences, Faculty of Medicine & Health, The University of Sydney, NSW,
9
2006, Australia.
10
2
Tuberculosis Research Program, Centenary Institute, Royal Prince Alfred Hospital,
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Camperdown, NSW, 2050, Australia.
12
3
Microbial Pathogenesis and Immunity Group, Department of Infectious Diseases and
13
Immunology, School of Medical Sciences, Faculty of Medicine & Health, University of Sydney,
14
NSW, 2006, Australia.
15
4
National Clinical Research Center for Infectious Diseases, Guangdong Key Laboratory of
16
Emerging Infectious Diseases, Shenzhen Third People’s Hospital, Southern
17
University of Science and Technology, Shenzhen, China.
18
5
Immune Imaging Program, Centenary Institute, Royal Prince Alfred Hospital, Camperdown,
19
NSW, 2050, Australia.
20
6
Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney,
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Sydney, NSW, 2006, Australia.
22
7
Liver Immunology Program, Centenary Institute, Royal Prince Alfred Hospital, Camperdown,
23
NSW, 2050, Australia.
24
8
AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown,
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NSW, 2050, Australia.
26
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* Corresponding author: Carl G Feng: carl.feng@sydney.edu.au
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(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprintthis version posted October 26, 2020. ; https://doi.org/10.1101/2020.10.25.353763doi: bioRxiv preprint

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Abstract:
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The quality of T cell responses depends on the lymphocytes’ ability to undergo clonal expansion,
31
acquire effector functions and traffic to the site of infection. Although TCR signal strength is
32
thought to dominantly shape the T cell response, by using TCR transgenic CD4
+
T cells with
33
different pMHC binding affinity, we reveal that TCR affinity does not control Th1 effector
34
function acquisition nor the functional output of individual effectors following mycobacterial
35
infection. Rather, TCR affinity calibrates the rate of cell division to synchronize the distinct
36
processes of T cell proliferation, differentiation and trafficking. By timing cell division-dependent
37
IL-12R expression, TCR affinity controls when T cells become receptive to Th1-imprinting IL-12
38
signals, determining the emergence and magnitude of the Th1 effector pool. These findings reveal
39
a distinct yet cooperative role for IL-12 and TCR signalling in Th1 differentiation and suggests
40
that the temporal activation of clones with different TCR affinity is a major strategy to coordinate
41
immune surveillance against persistent pathogens.
42
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Keywords:
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TCR affinity, TCR signal, Th1 response, cell division, IL-12, mycobacteria.
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(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprintthis version posted October 26, 2020. ; https://doi.org/10.1101/2020.10.25.353763doi: bioRxiv preprint

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Introduction:
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The successful containment of invading pathogens requires the rapid generation of large numbers
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of antigen-specific T cells with the correct effector function. This involves the activation of distinct
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programs, including T cell proliferation, differentiation, and migration. Failure in activating or
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regulating these programs results in impaired host defense. The majority of studies have focused
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on one or a limited number of CD4
+
T cell programs, such as, the magnitude of population
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expansion or expression of master regulators of transcription. There is little information available
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as to whether these processes, which operate at different biological scales spanning from the
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molecule to the tissue, are individually or cooperatively regulated in vivo. Indeed, in vitro studies
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have already suggested a link between cell division and differentiation, demonstrating that cell
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division progression is associated with increased expression of signature Th cytokines (1-3).
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The pool of naive T cells in vivo is diverse and contains clones that express distinct TCRs
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recognizing different peptide:MHC (pMHC) complexes. It is estimated that there are anywhere
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between twenty and one thousand naive T cells that possess the same pMHC specificity (4, 5),
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each with different binding affinities. The strength of TCR signals, regulated by the TCRs affinity,
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the density of pMHC and co-stimulatory molecules on antigen presenting cells (APCs), regulates
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downstream T cell activation and function (6, 7). While high affinity TCR signals in cytotoxic
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CD8
+
T lymphocytes accelerate cell division and prolong population expansion (8, 9), it delays
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their migration from secondary lymphoid organs (SLOs) (9, 10) resulting in impaired pathogen
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control (10). Similarly, strong TCR signals enhance the expansion of CD4
+
T cell populations (11-
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13).
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Defining the role of TCR signaling strength in the CD4
+
lymphocyte response is
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challenging because of the functional heterogeneity in helper T cell populations. The effector
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(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprintthis version posted October 26, 2020. ; https://doi.org/10.1101/2020.10.25.353763doi: bioRxiv preprint

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function of Th populations is instructed by signals from the TCR as well as from pathogen-
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conditioned accessory cells and APCs. Historically, investigations into Th cell differentiation have
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focused on “qualitative” T cell-extrinsic cytokine signals (7, 14). In the case of Th1 differentiation,
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the innate cytokine IL-12 promotes the generation of interferon-γ (IFN-γ)-producing effectors (15,
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16) and host survival following infection with intracellular pathogens (17). Recent studies have
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suggested a role for “quantitative” differences in TCR signal strength in regulating CD4
+
T cell
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differentiation (12, 18-20). Potent TCR signaling is associated with the generation of Th1 (18, 19)
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or Tfh cells (11, 20, 21). Mechanisms proposed to mediate strong TCR signal-driven Th lineage
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commitment vary depending on experimental settings. For example, IL-2 (12, 13, 19) and IL-12
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receptor signaling (18) have each been suggested to contribute to the generation of Th1 populations
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following potent TCR stimulation. The model-dependent function of strong TCR signaling
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suggests a potential interplay between quantitative TCR and qualitative environmental signals in
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instructing Th differentiation. Currently, the relative role of TCR and innate cytokine signals in
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lineage commitment and the mechanisms integrating these signals is unknown.
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In this study, we developed a T cell adoptive transfer model using CD4
+
T cells from two
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TCR transgenic (Tg) mouse lines that recognize the same epitope of the Mycobacterium
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tuberculosis protein Early Secretory Antigenic Target 6 (ESAT-6, E6), with different binding
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affinities. Following T cell transfer, WT or IL-12-deficient recipient mice were infected with a
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recombinant Mycobacterium bovis Bacillus Calmette-Guérin-expressing E6 (BCG-E6). By
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tracking transgenic CD4
+
T cells across multiple time-points and in different tissues following
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intravenous (i.v.) BCG infection, we reveal that by adjusting the rate of cell division, a major
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function of TCR affinity is to determine the speed and magnitude of the CD4
+
T cell response.
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Moreover, TCR affinity plays a minimal role in specifying T helper cell effector function.
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(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprintthis version posted October 26, 2020. ; https://doi.org/10.1101/2020.10.25.353763doi: bioRxiv preprint

5
However, by regulating cell division-dependent IL-12Rb2 expression, TCR affinity controls when
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T cells become receptive to IL-12 and acquire Th1 effector function. Since high affinity CD4
+
T
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cells also migrate to infected non-lymphoid tissues faster than their low affinity counterparts, our
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findings show that TCR affinity coordinates multiple programs to determine the overall potency
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of the Th cell response to infection. They also suggest that the temporal activation of distinct T
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cell clones is a mechanism controlling the initiation and maintenance of Th1 immunity against
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persistent infection.
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(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprintthis version posted October 26, 2020. ; https://doi.org/10.1101/2020.10.25.353763doi: bioRxiv preprint

Figures (6)
Citations
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01 Jan 2014
TL;DR: It is reported that T cell receptor and costimulatory signals imprint an early, cell-intrinsic, division fate, whereby cells effectively count through generations before returning automatically to a quiescent state, and provides a quantitative paradigm for therapeutically manipulating immune response strength.
Abstract: Tcell responses are initiated by antigen and promoted by a range of costimulatory signals. Understanding how Tcells integrate alternative signal combinations and make decisions affecting immune response strength or tolerance poses a considerable theoretical challenge. Here, we report that Tcell receptor (TCR) and costimulatory signals imprint an early, cell-intrinsic, division fate,whereby cells effectively count through generations before returning automatically to a quiescent state. This autonomous program can be extended by cytokines. Signals from the TCR, costimulatory receptors, and cytokines add together using a linear division calculus, allowing the strength of a Tcell response to be predicted from the sum of the underlying signal components.These data resolve a long-standing costimulation paradox and provide a quantitative paradigm for therapeutically manipulating immune response strength.

5 citations


References
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Journal ArticleDOI
Giorgio Trinchieri1Institutions (1)
TL;DR: The understanding of the relative roles of IL-12 and other factors in TH1-type maturation of both CD4+ and CD8+ T cells is discussed here, including the participation in this process ofIL-23 and IL-27, two recently discovered members of the new family of heterodimeric cytokines.
Abstract: Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that induces the production of interferon-gamma (IFN-gamma), favours the differentiation of T helper 1 (T(H)1) cells and forms a link between innate resistance and adaptive immunity. Dendritic cells (DCs) and phagocytes produce IL-12 in response to pathogens during infection. Production of IL-12 is dependent on differential mechanisms of regulation of expression of the genes encoding IL-12, patterns of Toll-like receptor (TLR) expression and cross-regulation between the different DC subsets, involving cytokines such as IL-10 and type I IFN. Recent data, however, argue against an absolute requirement for IL-12 for T(H)1 responses. Our understanding of the relative roles of IL-12 and other factors in T(H)1-type maturation of both CD4+ and CD8+ T cells is discussed here, including the participation in this process of IL-23 and IL-27, two recently discovered members of the new family of heterodimeric cytokines.

3,393 citations


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23 Apr 1993-Science
TL;DR: This regulatory pathway may have evolved to enable innate immune cells, through interactions with microbial pathogens, to direct development of specific immunity toward the appropriate TH1 phenotype.
Abstract: Development of the appropriate CD4+ T helper (TH) subset during an immune response is important for disease resolution. With the use of naive, ovalbumin-specific alpha beta T cell receptor transgenic T cell, it was found that heat-killed Listeria monocytogenes induced TH1 development in vitro through macrophage production of interleukin-12 (IL-12). Moreover, inhibition of macrophage production of IL-12 may explain the ability of IL-10 to suppress TH1 development. Murine immune responses to L. monocytogenes in vivo are of the appropriate TH1 phenotype. Therefore, this regulatory pathway may have evolved to enable innate immune cells, through interactions with microbial pathogens, to direct development of specific immunity toward the appropriate TH phenotype.

3,136 citations


Journal ArticleDOI
Peter B. Schiff1, Susan Band HorwitzInstitutions (1)
TL;DR: Taxol inhibited the migration behavior of fibroblast cells, but these cells did not lose their ability to produce mobile surface projections such as lamellipodia and filopodia.
Abstract: Taxol, a potent inhibitor of human HeLa and mouse fibroblast cell replication, blocked cells in the G2 and M phase of the cell cycle and stabilized cytoplasmic microtubules. The cytoplasmic microtubules of taxol-treated cells were visualized by transmission electron microscopy and indirect immunofluorescence microscopy. More than 90% of the cells treated with 10 micro M taxol for 22 hr at 37 degrees C displayed bundles of microtubules that appeared to radiate from a common site (or sites), in addition to their cytoplasmic microtubules. Untreated cells that were kept in the cold (4 degrees C) for 16 hr lost their microtubules, whereas cells that were pretreated with taxol for 22 hr at 37 degrees C continued to display their microtubules and bundles of microtubules in the cold. Taxol inhibited the migration behavior of fibroblast cells, but these cells did not lose their ability to produce mobile surface projections such as lamellipodia and filopodia.

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Journal ArticleDOI
Maryam Afkarian1, John R. Sedy1, Jianfei Yang1, N. G. Jacobson1  +4 moreInstitutions (1)
TL;DR: T-bet is induced by IFN-γ and STAT1 signaling during T cell activation and mediates STAT1-dependent processes of TH1 development, including the induction of IL-12Rβ2.
Abstract: T helper type 1 (T(H)1) cell development involves interferon-gamma (IFN-gamma) signaling through signal transducer and activator of transcription 1 (STAT1) and interleukin-12 (IL-12) signaling through STAT4 activation. We examined here T-bet regulation and evaluated the actions of T-bet in STAT1- and STAT4-dependent T(H)1 development processes. We found that T-bet expression during T cell activation was strongly dependent on IFN-gamma signaling and STAT1 activation, but was independent of STAT4. Ectopic T-bet expression strongly increased IFN-gamma production in T(H)2 cells activated by PMA-ionomycin, but weakly increased IFN-gamma production in T(H)2 cells stimulated by IL-12 IL-18 or OVA peptide antigen-presenting cell stimulation. In contrast, IL-12 IL-18 induced IFN-gamma production remained STAT4-dependent despite ectopic T-bet expression. Ectopic T-bet expression selectively induced expression of IL-12Rbeta2, but not IL-18Ralpha, in wild-type and STAT1(-/-) T(H)2 cells, but did not extinguish expression of GATA-3 and T(H)2 cytokines. Finally, ectopic T-bet did not directly induce expression of endogenous T- bet independently of IFN-gamma or STAT1. Thus, T-bet is induced by IFN-gamma and STAT1 signaling during T cell activation. In addition, T-bet mediates STAT1-dependent processes of T(H)1 development, including the induction of IL-12Rbeta2.

969 citations


Journal ArticleDOI
01 May 1996-Immunity
TL;DR: It is indicated that IL-12 plays an essential role in regulating IFNγ production and in facilitating normal DTH responses and other phenomena associated with Th1 responses and cell-mediated immunity, i.e., IL-2 secretion and CTL generation, were not compromised in the absence of IL- 12.
Abstract: IL-12 is a cytokine that can exert regulatory effects on T and NK cells and promote Th1 responses. To delineate further the physiologic role of IL-12 in immunity, mice deficient for this cytokine were generated. IL-12-deficient mice were impaired but not completely lacking in the ability to produce IFNγ following endotoxin administration and to mount a Th1 response in vivo, as measured by antigen-induced IFNγ secretion by immune lymph node cells in vitro. In contrast, secretion of IL-4 was enhanced, while proliferation and secretion of IL-2 and IL-10 were normal following antigen stimulation. DTH responses were significantly reduced in IL-12-deficient mice, but no defect in allogeneic CTL responses was observed. These results indicate that IL-12 plays an essential role in regulating IFNγ production and in facilitating normal DTH responses. However, other phenomena associated with Th1 responses and cell-mediated immunity, i.e., IL-2 secretion and CTL generation, were not compromised in the absence of IL-12.

967 citations


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