June 30, 2022

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Medical Knowledge: Details about  T cell checkpoints

Medical Knowledge: Details about  T cell checkpoints



Medical Knowledge:  Details about  T cell checkpoints.

Research over the past 50 years has shown that T lymphocytes exhibit remarkable diversity in terms of developmental origin, differentiation trajectories, migration and residence patterns, and effector, cytotoxic, and suppressive activities.

Multiple negative regulators have been identified during T cell development and function, collectively referred to as ” T cell tolerance “.

“Central tolerance” describes the mechanisms of selection during thymocyte differentiation that shape the pool of cells that limit the survival of self-reactive cells, while peripheral tolerance is maintained by multiple mechanisms that inhibit the response of peripheral T cells to self-antigens Reaction.

Studies have shown that the thymus is only about 60-70% efficient at removing autoreactive T cells, leaving the peripheral naive T cell pool with a large population of low-affinity, autoreactive T cells. These T cells pose a potential risk of autoimmune reactions.

To avoid damage to host tissues, the fate of these cells is determined by a series of checkpoints that regulate the quality and extent of T cell-mediated immunity, called tolerance checkpoints .

Medical Knowledge:  Details about  T cell checkpoints

During the naive T cell stage, two intrinsic checkpoints that actively maintain tolerance are quiescence and neglect .

Anergy is a major hallmark of T cells in the absence of co-stimulatory T cell activation .

When T cells are successfully activated to exert their effects, exhaustion and senescence can limit excessive inflammation and prevent immunopathology.

At each stage of the T-cell journey, cell death is a checkpoint that limits clonal expansion and terminates unrestricted responses.

Quiescence

Quiescence is a peripheral tolerance mechanism that limits the response of naive T cells to strong signals.

Quiescence is also an active process that maintains T cells in the G0 phase of the cell cycle, maintaining a smaller cell size, ensuring lower cellular metabolism, and preventing the development of effector functions.

Quiescence plays a key role in clonal selection, ensuring that the majority of cells that bind a particular antigen are suppressed and limiting the expansion of clones to high-affinity clones.

Numerous molecular effectors involved in T cell quiescence have been identified that control a diverse range of biological pathways.

TGFβ-1 and TOB1 , two effectors of the transforming growth factor-β superfamily, downregulate IL-2 production and T cell activation through downstream signaling through SMAD.

Resting T cells highly express the DNA-binding protein KLF2 , making it a marker of T cell quiescence.

KLF2 maintains T cell quiescence in part by inhibiting the transcription factor MYC and affecting cell cycle progression through p21.

The expression of KLF2 is induced and maintained by the transcription factor FOXO1, which has a well-established role in maintaining T cell quiescence.

Furthermore, expression of the inhibitory checkpoint receptor VISTA appears to be critical for naive T cells to maintain a quiescent state.

Studies have shown that VISTA − T cells express reduced levels of important quiescent effector molecules, such as KLF2, BTG1, and BTG2.

Neglect

Neglect is another tolerance checkpoint at the naive T cell stage observed in multiple systems, but the mechanism remains unclear.

Simply put, despite the presence of specific autoantigens, autoreactive T cells may fail to activate and initiate autoimmune disease. These T cells are still in a naive, responsive state.

Mechanisms that control neglect can include intrinsic and extrinsic mechanisms. Intrinsic mechanisms include the affinity of TCRs for antigens, where TCR affinity is too low to elicit a T-cell response. Extrinsic mechanisms may include lack of T-cell stimulation due to low antigen density and/or limited antigen recognition due to their anatomical location.

A notable difference between quiescence and neglect is that quiescence is a universal marker of tolerance for all naive T cells regardless of their antigen specificity, whereas ‘neglect’ refers to avoiding activation of specific autoreactive T cells, host tissue and the location of the autoantigen is the determining factor.

Anergy

Mechanisms of quiescence, neglect, and anergy all limit naive T cell responses to antigens.

However, quiescence is maintained in a manner agnostic to TCR stimulation, neglect is the result of antigens being hidden or presented at extremely low levels, and anergy is a direct result of “unbalanced” TCR stimulation in naive T cells.

Anergy is the closest non-deletion tolerance mechanism following TCR engagement and is functionally defined as the hyporesponsiveness of T cells to restimulation under conditions of intense stimulation.

Functionally, it is an early checkpoint in T cell priming, preventing potential T cell pathogenicity before the T cell effector phase begins.

At the molecular level, anergy is caused by co-stimulatory-deficient ( tolerance ) TCR activation.

In normal co-stimulatory ( e.g. CD28 ) T cells receiving TCR signaling, the induced transcription factor NFAT1, together with AP-1, induces T cell differentiation and effector function.

In contrast, tolerogenic TCR activation results in defective RAS–MAPK signaling, which in turn impairs the translocation of AP-1 to the nucleus.

In this case, only an imbalance in NFAT1 activation resulted in the induced expression of several genes involved in anergy-state proteins, such as diacylglycerol kinase-α ( DGKα ) and the regulatory ubiquitin ligase CBLB.

The hallmark functional changes that define anergy include marked reductions in IL-2, INF-γ, and TNF levels upon TCR stimulation.

This acquired refractory state is associated with growth arrest and defects in cell cycle progression.

Although anergy is persistent, it is reversible, and in vivo studies have shown that in the absence of antigen, anergic T cells slowly recover functional responses, suggesting that prolonged antigen exposure is required to maintain anergy.

Exhausted

T-cell depletion is a major non-deletion tolerance mechanism in the T-cell effector phase. Compared with fully functional Teff cells, Tex cells were less responsive to antigen at multiple levels, but not absent.

Tex cells are characterized by

(1) reduced cytokine production,

(2) persistently high levels of inhibitory receptor expression,

(3) altered epigenetic, metabolic, and transcriptional states, and, importantly,

(4) an inability to transition to Rest-like cell state observed in memory T cells.

Preliminary studies on the phenotype of Tex cells found that these cells express multiple inhibitory receptors, including PD1, LAG3, TIGIT, CD38, CD39, and TIM3.

In fact, these receptors are not unique to Tex cells, and distinguishing Tex from anergic T cells based on surface markers is difficult because these two states of T cell dysfunction overlap in the expression of several inhibitory receptors.

The key difference between anergy and exhaustion is that anergic T cells arise early after T cell activation and priming, whereas Tex cells are generated from activated Teff cells at the effector stage.

Furthermore, the nature of the signals that induce these cellular stages differs.

Anergy is the product of co-stimulatory-deficient T-cell activation, whereas exhaustion is caused by chronic TCR stimulation in the presence of appropriate co-stimulatory signals.

At the molecular level, both anergic T cells and Tex cells express NFAT1 as an important driver of tolerance.

However, the canonical gene expression profile of Tex cells also appears to be determined by a complex transcription factor profile that includes decreased expression of TCF7 and increased expression of TOX, NR4A, BATF, IRF4, BLIMP1, and others.

Senescence

Senescence is defined as the phase of growth and proliferation arrest induced when “cells reach the end of their replicative potential or are exposed to various stressors”.

Studies on primary human T cells have shown that senescent T cells are low-proliferative, well-differentiated T cells that display the surface markers CD45RA, KLRG1, and CD57, but do not express the co-stimulatory receptors CD27 and CD28.

Unlike Tex cells, senescent T cells are not impaired in effector function but acquire a senescence-associated secretory phenotype characterized by the production of high levels of proinflammatory and inhibitory cytokines.

From an evolutionary perspective, senescence may prevent the development of T-cell lymphomas by preventing DNA-damaged T cells from proliferating excessively.

Another benefit may be local control of excessive inflammation during chronic autoimmunity or infection.

The aging tolerance checkpoint is likely to become increasingly important as human life expectancy increases, as older adults become more susceptible to infections to which they were previously immune.

With age, immunity is significantly reduced, and one of the main factors leading to the decline in immunity is the impairment of T cell function.

Therefore, more in vivo mechanistic studies in multiple settings are needed to identify and elucidate the relevance of this tolerance checkpoint.

Death

Multiple programmed cell death checkpoints exist at several stages of the T cell journey.

Molecular mechanism studies on tolerogen-induced death of naive T cells show that cell death is mediated through an endogenous pro-apoptotic family member, BIM, which is distinct from exogenous apoptosis mediated by death receptors such as FAS way.

High-resolution transcriptional profiling of mouse T cells under tolerized and immune conditions revealed distinct molecular signatures prior to apoptosis: this includes Rankl ( Tnfsf11 ), Bim ( Bcl2l11 ), and Nr4a family members Nr4a1, Nr4a2, and Nr4a3 among other genes.

Upregulation, as well as downregulation of the cytokine receptor IL-7Rα, all of these changes may lead to T cell death.

The second peripheral death checkpoint occurs when activated Teff cells are restimulated, leading to activation-induced cell death ( AICD ).

This cell death mechanism is induced by the extrinsic apoptotic pathway through death receptors ( most commonly described as FAS, but also including TNFR1, TRAILR1 and TRAILR2 ).

This peripheral deletion mechanism acts as a self-limiting feedback process that controls T cell expansion and is critical for the clonal shrinkage process in which antigen-specific Teff cells are eventually eliminated during termination of the immune response.

In addition to apoptosis, peripheral blood T cell tolerance may be associated with multiple T cell death mechanisms.

An example is necroptosis ( also called “programmed necrosis”, which is caspase-independent and kinase RIPK3-dependent ); ferroptosis ( an iron-dependent programmed cell death ) is through the accumulation of ROS As a result, the accumulation of ROS leads to membrane lipid peroxidation and subsequent cell death.

Despite the complex multiple networks of death pathways in T cell biology, this tolerance checkpoint mechanism remains the most effective and reliable means of inhibiting T cell expansion at nearly every stage of T cell activity.

It can control the size and timing of the immune response, thereby preventing the occurrence of T cell-mediated immune pathology.


Summary

T-cell tolerance is regulated by multiple mechanisms that work in concert to achieve constitutive and negative feedback regulatory mechanisms and set a robust barrier to pathological inflammation.

However, there are unanswered questions about the relative contributions of these mechanisms to protection and immune dysregulation.

For example, it is unclear how the constitutive regulators of naive T cell quiescence cooperate to maintain this state, and the molecular activities of most relevant factors remain elusive.

Another unclear aspect is the role of anergy, death, and exhaustion in the induction of tumor T-cell tolerance.

Additionally, we still do not know the potential contribution of cell death mechanisms such as necroptosis and ferroptosis to T cell fate and regulation.

We have now reached a stage where the complex phenotype of immune cells enables unprecedented levels of resolution of cellular states, including multiple T-cell tolerance states in the same model system, with fine temporal resolution.

This makes it possible to answer the question: What tolerance mechanisms dominate in each setting? What kind of regulators are at work?

References:

1.Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey. Nat Rev Immunol. 2020 Oct 19

Medical Knowledge:  Details about  T cell checkpoints

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