Editing Clonal anergy (section)

==Molecular mechanism of anergy induction in T lymphocytes==
Understanding the molecular mechanism of anergy induction in [[T cell|T lymphocytes]] unveils the intricate interplay of signaling pathways governing immune responses. Upon stimulation, the [[T cell receptor]] (TCR) in conjunction with co-stimulatory receptors orchestrates a comprehensive activation of all the [[T cell|T-cell]]’s signaling pathways, collectively termed full T-cell stimulation. Among these pathways, the calcium-dependent arm of lymphocyte signaling is particularly pivotal, triggered by [[T cell receptor|TCR]] engagement. This initiates a cascade culminating in an elevation of intracellular [[Calcium|Ca<sup>+II</sup>]] concentration,<ref name="Macián et al">{{cite journal |vauthors=Macián F, García-Cózar F, Im SH, Horton HF, Byrne MC, Rao A |date=June 2002 |title=Transcriptional mechanisms underlying lymphocyte tolerance |journal=Cell |volume=109 |issue=6 |pages=719–731 |doi=10.1016/S0092-8674(02)00767-5 |pmid=12086671 |doi-access=free}}</ref> a critical event in T cell activation. Under such conditions, the calcium-dependent phosphatase [[calcineurin]] acts on the [[transcription factor]] [[NFAT]], facilitating its translocation to the nucleus, where it regulates gene expression.

Expanding upon this complexity, during full [[T cell|T-cell]] stimulation the [[Co-stimulation|co-stimulatory]] receptor [[CD28]] activates [[Phosphoinositide 3-kinase|PI3K]] and other pathways, augmenting the nuclear levels of key transcription factors such as [[REL|rel]], [[NF-kappaB|NF-κB]] and [[AP-1 transcription factor|AP-1]] beyond those induced by TCR activation alone.<ref name="Macián et al" /> The formation of [[AP-1 transcription factor|AP-1]], [[C-Fos|fos]]/[[C-jun|jun]] heterodimer, further complexes with [[NFAT]], creating a transcriptional complex crucial for the expression of genes<ref name="Rudensky et al">{{cite journal |vauthors=Rudensky AY, Gavin M, Zheng Y |date=July 2006 |title=FOXP3 and NFAT: partners in tolerance |journal=Cell |volume=126 |issue=2 |pages=253–256 |doi=10.1016/j.cell.2006.07.005 |pmid=16873058 |doi-access=free}}</ref> associated with [[T cell|T-cell]] productive responses, including [[Interleukin 2|IL-2]] and its [[IL-2 receptor|receptor]].<ref name="Rudensky et al" />

In contrast, [[T cell receptor|TCR]] signaling in the absence of co-stimulatory receptors predominantly activates the calcium arm of the signaling pathway, leading to [[NFAT]] activation alone. However, without the concurrent induction of [[AP-1 transcription factor|AP-1]] by other pathways, [[NFAT]] fails to form the transcriptional complex necessary for a productive [[T cell|T-cell]] response. Instead, [[NFAT]] homodimerizes, functioning as a transcriptional factor that induces anergy in the lymphocyte.<ref name="Soto-Nieves et al">{{cite journal |vauthors=Soto-Nieves N, Puga I, Abe BT, Bandyopadhyay S, Baine I, Rao A, Macian F |date=April 2009 |title=Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance |journal=The Journal of Experimental Medicine |volume=206 |issue=4 |pages=867–876 |doi=10.1084/jem.20082731 |pmc=2715123 |pmid=19307325}}</ref>

[[NFAT]] homodimers play a direct role in the expression of anergy-associated genes, such as the ubiquitin ligase [[RNF128|GRAIL]] and the protease [[caspase 3]].<ref name="Soto-Nieves et al" /> Furthermore, anergized cells exhibit decreased expression levels of [[Interleukin 2|IL-2]], [[Tumor necrosis factor alpha|TNFα]], and [[Interferon gamma|IFNγ]], characteristic of a productive response, while favoring the production of the anti-inflammatory cytokine [[Interleukin 10|IL-10]].<ref name="Macián et al" /> Although three [[NFAT]] proteins - NFAT1, NFAT2 and NFAT4 - are preset in T-cells, they demonstrate redundancy to some extent.<ref name="Soto-Nieves et al" />

In the context of antigen presentation by [[Antigen-presenting cell|antigen-presenting cells]] (APC), [[T cell|T lymphocytes]] undergo a productive response when the antigen is appropriately presented, activating T cell co-stimulatory receptors. However, encountering antigens not presented by the [[Antigen-presenting cell|APCs]] or weakly presented antigens induces anergic responses in T cells.<ref name="Soto-Nieves et al" /> Notably, strong stimulation through [[Interleukin 2|IL-2]] or [[T cell receptor|TCR]]/co-stimulatory receptors can overcome anergy, highlighting the dynamic nature of immune regulation.<ref name="Macián et al" /><ref name="Rudensky et al" />

Moreover, recent research has illuminated the role of regulatory T cells (Tregs) in modulating T cell responses and maintaining immune tolerance. Tregs, characterized by the expression of the transcription factor Foxp3, exert immunosuppressive effects by inhibiting the activation and function of effector T cells.<ref name="Soto-Nieves et al" /> Importantly, Tregs can directly interact with anergic T cells, further reinforcing their state of unresponsiveness and promoting peripheral tolerance. This interaction involves various mechanisms, including the secretion of inhibitory cytokines such as IL-10 and TGF-β, as well as cell-contact-dependent suppression mediated by molecules like CTLA-4.<ref name="Macián et al" /> Understanding the intricate crosstalk between Tregs and anergic T cells provides valuable insights into the maintenance of immune homeostasis and has implications for therapeutic strategies aimed at modulating immune responses in autoimmune diseases and transplantation.<ref name="Rudensky et al" /><ref name="Soto-Nieves et al" />