Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types.
Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types.
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DOI：
10.3389/fimmu.2020.608024
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发表时间：
2020
影响因子：
7.3
通讯作者：
Decker WK
中科院分区：
文献类型：
--
作者：
Oyewole-Said D;Konduri V;Vazquez-Perez J;Weldon SA;Levitt JM;Decker WK
免疫反应由一个微调程序组成，无论何时启动，其激活必须与抑制机制相结合。这确保了对有益的抗病原体和抗肿瘤反应的严格控制，同时保持组织完整性，促进组织修复，并防止自身免疫。这种二元反应的一个令人信服的例子是在调节T细胞反应的强度和类型中共刺激和共抑制信号传导的动员。特别重要的是被CTLA-4对抗的共刺激分子CD 28。虽然CD 28在免疫应答中的作用已被彻底阐明，但CTLA-4生物学的许多方面仍存在争议。CD 28的表达在很大程度上受限于T细胞中的组成型表达，因此，通过有限和特异性的表达谱已经在一定程度上简化了其功能的梳理。另一方面，CTLA-4的表达虽然主要在T细胞中报道，但也在淋巴和骨髓谱系内的多种细胞库以及肿瘤表面上进行了描述。尽管如此，CTLA-4的功能主要在T细胞生物学的背景下描述。对T细胞生物学的关注可能是CD 28和CTLA-4的高度氨基酸序列同源性和共表达模式的直接结果，这最初导致发现CTLA-4作为CD 28的反受体（已经描述了其T细胞活化作用）。此外，CTLA-4在Treg介导的免疫抑制中的巨大作用以及CTLA-4−/−小鼠中T细胞过度增殖和由此产生的疾病的惊人表型的观察有助于在CTLA-4的研究中适当地以T细胞为中心。然而，CTLA-4生物学的完整阐明可能需要对其在T细胞以外的背景下的作用有更细致的理解。鉴于抗CTLA-4抗体在治疗癌症中的显著但有限的效用以及CTLA-4-IG在自身免疫性疾病如类风湿性关节炎中的显著但有限的效用，这是特别有意义的。通过充分推导CTLA-4调节的免疫稳态的生物学，可以解决阻碍基于CTLA-4的免疫疗法的广泛适用性的瓶颈。
The immune response consists of a finely-tuned program, the activation of which must be coupled with inhibitory mechanisms whenever initiated. This ensures tight control of beneficial anti-pathogen and anti-tumor responses while preserving tissue integrity, promoting tissue repair, and safeguarding against autoimmunity. A cogent example of this binary response is in the mobilization of co-stimulatory and co-inhibitory signaling in regulating the strength and type of a T-cell response. Of particular importance is the costimulatory molecule CD28 which is countered by CTLA-4. While the role of CD28 in the immune response has been thoroughly elucidated, many aspects of CTLA-4 biology remain controversial. The expression of CD28 is largely constrained to constitutive expression in T-cells and as such, teasing out its function has been somewhat simplified by a limited and specific expression profile. The expression of CTLA-4, on the other hand, while reported predominantly in T-cells, has also been described on a diverse repertoire of cells within both lymphoid and myeloid lineages as well as on the surface of tumors. Nonetheless, the function of CTLA-4 has been mostly described within the context of T-cell biology. The focus on T-cell biology may be a direct result of the high degree of amino acid sequence homology and the co-expression pattern of CD28 and CTLA-4, which initially led to the discovery of CTLA-4 as a counter receptor to CD28 (for which a T-cell-activating role had already been described). Furthermore, observations of the outsized role of CTLA-4 in Treg-mediated immune suppression and the striking phenotype of T-cell hyperproliferation and resultant disease in CTLA-4−/− mice contribute to an appropriate T-cell-centric focus in the study of CTLA-4. Complete elucidation of CTLA-4 biology, however, may require a more nuanced understanding of its role in a context other than that of T-cells. This makes particular sense in light of the remarkable, yet limited utility of anti-CTLA-4 antibodies in the treatment of cancers and of CTLA-4-Ig in autoimmune disorders like rheumatoid arthritis. By fully deducing the biology of CTLA-4-regulated immune homeostasis, bottlenecks that hinder the widespread applicability of CTLA-4-based immunotherapies can be resolved.
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DOI：
10.4049/jimmunol.1401876
发表时间：
2015-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hou TZ;Qureshi OS;Wang CJ;Baker J;Young SP;Walker LS;Sansom DM
通讯作者：
Sansom DM
影响因子：
2.9
作者：
Bradshaw, JD;Lu, P;Kurtz, SE
通讯作者：
Kurtz, SE
影响因子：
3.7
作者：
Fathima, Nusrath;Narne, Parimala;Ishaq, Mohammed
通讯作者：
Ishaq, Mohammed
影响因子：
64.8
作者：
BRUNET, JF;DENIZOT, F;GOLSTEIN, P
通讯作者：
GOLSTEIN, P
影响因子：
4.4
作者：
Baroja, ML;Vijayakrishnan, L;Kuchroo, VK
通讯作者：
Kuchroo, VK