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Review
. 2020 Sep:355:104173.
doi: 10.1016/j.cellimm.2020.104173. Epub 2020 Jul 15.

Tolerogenic vaccines: Targeting the antigenic and cytokine niches of FOXP3+ regulatory T cells

Mark D Mannie  1 , Kayla B DeOca  2 , Alexander G Bastian  2 , Cody D Moorman  2
Affiliations
Review

Tolerogenic vaccines: Targeting the antigenic and cytokine niches of FOXP3+ regulatory T cells

Mark D Mannie et al. Cell Immunol. 2020 Sep.

Abstract

FOXP3+ regulatory T cells (Tregs) constitute a critical barrier that enforces tolerance to both the self-peptidome and the extended-self peptidome to ensure tissue-specific resistance to autoimmune, allergic, and other inflammatory disorders. Here, we review intuitive models regarding how T cell antigen receptor (TCR) specificity and antigen recognition efficiency shape the Treg and conventional T cell (Tcon) repertoires to adaptively regulate T cell maintenance, tissue-residency, phenotypic stability, and immune function in peripheral tissues. Three zones of TCR recognition efficiency are considered, including Tcon recognition of specific low-efficiency self MHC-ligands, Treg recognition of intermediate-efficiency agonistic self MHC-ligands, and Tcon recognition of cross-reactive high-efficiency agonistic foreign MHC-ligands. These respective zones of TCR recognition efficiency are key to understanding how tissue-resident immune networks integrate the antigenic complexity of local environments to provide adaptive decisions setting the balance of suppressive and immunogenic responses. Importantly, deficiencies in the Treg repertoire appear to be an important cause of chronic inflammatory disease. Deficiencies may include global deficiencies in Treg numbers or function, subtle 'holes in the Treg repertoire' in tissue-resident Treg populations, or simply Treg insufficiencies that are unable to counter an overwhelming molecular mimicry stimulus. Tolerogenic vaccination and Treg-based immunotherapy are two therapeutic modalities meant to restore dominance of Treg networks to reverse chronic inflammatory disease. Studies of these therapeutic modalities in a preclinical setting have provided insight into the Treg niche, including the concept that intermediate-efficiency TCR signaling, high IFN-β concentrations, and low IL-2 concentrations favor Treg responses and active dominant mechanisms of immune tolerance. Overall, the purpose here is to assimilate new and established concepts regarding how cognate TCR specificity of the Treg repertoire and the contingent cytokine networks provide a foundation for understanding Treg suppressive strategy.

Keywords: Clonotypic specificity; FOXP3(+) Tregs; Immunological tolerance; T cell antigen receptor; Tolerogenic vaccination.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1:
Figure 1:. The modus operandi of CD4+ FOXP3+ CD25high Tregs:
The defining hallmark of FOXP3+ Tregs is the functional coupling of TCR specificity for agonistic self, chronic activation in response to self, and suppression of Tcon-mediated reactions against self. Quiescent Tregs (green) are selected in the thymus and periphery to recognize self-MHC ligands as intermediate-efficiency agonistic ligands, which is postulated to maintain viability of FOXP3+ Tregs and elicit high surface expression of CD25. Rogue Tcons (red) that have the potential to mediate autoimmune pathogenesis recognize agonistic self-MHC ligands and produce IL-2, which is a source of paracrine IL-2 for Tregs. In this environment, Tregs receive two signals including agonistic TCR ligation and paracrine IL-2 stimulation. Due to their superlative CD25 expression, Tregs monopolize the local IL-2 supply to drive Treg growth while depriving Tcons of the IL-2 needed for effector function and survival. Aside from sequestering IL-2, activated effector Tregs use multiple direct and indirect mechanisms to block Tcon-mediated autoimmune pathogenesis.
Figure 2:
Figure 2:. The antigen-dependent selection of the T cell repertoire:
A quantitative continuum conceptualized by four zones of TCR ligation efficiencies shape the emerging T cell repertoire during thymic selection with each zone associated with a unique fate. (A) Death by neglect: Thymocytes that lack recognition of any self-MHC/ peptide complex die in the thymus due to the lack of homeostatic signaling. (B) Positive thymic selection: Thymocytes that experience relatively weak, non-activating TCR engagement receive requisite homeostatic signaling and emerge from the thymus as the mature Tcon repertoire. These Tcons continue to recognize positively-selecting self MHC/ peptide ligands in peripheral tissues as requisite survival signals. Many Tcons are thought to establish tissue residence at sites where these clones detect high concentrations of cognate self MHC/ peptide complexes. (C) Agonist selection: Thymocytes that experience intermediate-efficiency agonistic TCR engagement receive requisite survival signaling and emerge from the thymus as the mature Treg repertoire. These Tregs continue to recognize cognate self MHC/ peptide ligands in peripheral tissues as requisite survival signals. Many Tregs are thought to establish tissue residence at sites where these clones detect high concentrations of cognate self MHC/ peptide complexes. (D) Negative thymic selection: Thymocytes that recognize self-MHC/ peptide complex as high-efficiency agonistic ligands die in the thymus due to excess agonistic signaling. (E-F) Tcons and Tregs may cross-react and recognize foreign antigens as strong agonists and contribute to host defense.
Figure 3:
Figure 3:. T cell tissue-specific residency strategized by TCR specificity and antigen recognition efficiency.
TCR specificity and antigen recognition efficiency are thought to guide T cell homing, tissue residency, and function in peripheral tissues. (A, D) Tcon recognition of high-efficiency agonistic antigens is hypothesized to maintain immunogenic sentinel memory T cells at sites that will likely become routes of future infection. (B) Treg recognition of intermediate-efficiency agonistic self-antigens is hypothesized to provide homeostatic survival signals that guide homing and survival while maintaining phenotypic and functional stability of tissue-resident Tregs. (C) Tcon recognition of peripheral self-antigens as low-efficiency non-agonistic ligands (i.e. the positive-selecting MHC-ligands of positive thymic selection) is hypothesized to provide homeostatic survival signals that guide homing and survival of the Tcon repertoire. (E) Inflammatory conditions may amplify a low-efficiency homeostatic TCR recognition into an intermediate TCR efficiency signaling mode that favors naïve Tcon differentiation into Tregs to counter epitope spread to tissue-specific self-antigens.
Figure 4:
Figure 4:. Antigen complexity theory:
Most foreign pathogens are antigenically complex entities that present MHC-peptide ligands that are highly diverse and strongly-agonistic to collectively stimulate the robust activation of a diverse polyclonal Tcon repertoire. Rather than reflecting independent binary decisions between a single APC and a single Tcon, antigen complexity theory postulates that the immune system integrates decisions encompassing inputs from local T cell and APC populations to provide a consensus output. According to this postulated mechanism, Tcons or Tregs recognize cognate MHC-ligands on the surface of an APC and provide stimulatory or inhibitory feedback signals to the APC. The APC in turn collectively integrates the diverse signals and provides consensus costimulatory or tolerogenic signaling to the T cells in direct contact with that APC or to T cells in the local environment via cytokine production. (A) High diversity of strong agonistic peptides drives high frequencies of activated Tcons that provide collective feedback to the APC to drive robust costimulatory signaling by APCs, thereby overcoming inhibitory inputs from the Treg population. (B) Conversely, in the presence of low frequencies of strong agonistic peptides, the low frequencies of activated Tcons do not surpass thresholds requisite for costimulatory signaling by APCs, and dominant inhibitory inputs from the Treg population drive tolerogenic Treg responses. When Tregs are dominant, tolerogenic APCs and local Tregs mediate bystander inhibition of activated Tcons and mediate de novo differentiation of naïve Tcons into Tregs (i.e., infectious tolerance).
Figure 5:
Figure 5:. Antigenic complexity and IL-2 dependent control of the Tcon/ Treg balance.
Naïve Tcons and rested memory/ effector Tcons respond to agonistic antigen by producing IL-2, whereas chronically activated Tcons and Tregs lack capacity for antigen-stimulated IL-2 production. (A) Given persistence of high antigenic complexity in a local tissue, newly immigrating naïve and rested effector/ memory Tcons represent the main sources for the local supply of paracrine IL-2 needed to sustain pre-existing populations of tissue-resident effector Tcons and Tregs. In the presence of high antigenic complexity, the sustained consistent immigration of new Tcons will provide an abundant supply of IL-2 to establish high-zone IL-2 concentrations ensuring Tcon dominance and immunogenic responses. (B) In the presence of low antigenic complexity, the sporadic inconsistent immigration of new Tcons will provide a limited supply of IL-2 to establish low-zone IL-2 concentrations ensuring Treg dominance and tolerogenic responses.
Figure 6:
Figure 6:. Tolerogenic vaccination: bridging holes in the Treg repertoire to enhance bystander inhibition and infectious tolerance.
Tolerogenic vaccination must target pathogenic T cell clonotypes without knowledge of the pathogenic epitopes. For example, if pathogenesis in MS is driven by NAg3, 4, 5, and X, then CNS-derived DCs will present these pathogenic NAgs together with myriads of other NAgs because CNS tissue destruction releases diverse NAgs including endogenous versions of the vaccine NAgs. As a result, local DCs will present diverse NAgs including the unknown pathogenic NAgs and the known vaccine-specific NAgs (i.e., not derived from the vaccine per se but derived from damaged myelin). Upon tolerogenic vaccination with nonpathogenic NAg1 and NAg2, peripheral DCs will drive expansion of NAg1/2-specific Tregs, which will migrate throughout the body and home into tissues bearing high endogenous concentrations of NAg1 and NAg2. DCs presenting damage-associated CNS NAg3, 4, 5, and X represent the interface of vaccine-generated Tregs with pathogenic Tcons. This interface is the checkpoint that re-establishes tolerance (A) by reinforcing bystander inhibition of pathogenic Tcons and (B) by eliciting infectious tolerance via de novo differentiation of naïve tissue-resident Tcons into Tregs.
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