The key to precise targeted immunotherapy for tumors: T cell receptor antigen screening techniques / 中国肿瘤生物治疗杂志

@#[摘 要] 过继性T细胞疗法在实体瘤治疗中展现了良好的前景，成为目前肿瘤治疗领域的一大研究热点。其中，TCR-T疗法主要通过T细胞受体（TCR）与抗原肽-主要组织相容性复合体（pMHC）的特异性识别，进而激活过继性T细胞的抗肿瘤免疫反应。因此，全面解析TCR所靶向的抗原信息有助于提高TCR-T疗法在临床应用中的有效性及安全性。然而，高效、高通量的TCR抗原筛选技术的缺乏限制了TCR-T疗法的发展。近年来，随着高通量测序技术、质谱流式细胞技术和计算生物学的快速发展，研究人员开发了多种TCR抗原筛选技术用于解析TCR及其特异性识别的抗原信息。本文从抗原定向筛选、TCR定向筛选以及双向筛选三方面对TCR抗原筛选技术进行归纳总结，系统介绍其优缺点，展望TCR抗原筛选技术领域的发展前景，为未来抗原筛选技术的开发提供了新思路。

CRISPR/Cas9-mediated endogenous TCR knockout enhances TCR-T cells targeted killing HPV16-positive cervical cancer cells / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：基于CRISPR/Cas9基因编辑技术制备无内源TCR的TCR-T细胞并鉴定其在体外杀伤HPV16阳性宫颈癌SiHa细胞的功能。方法：培养健康志愿者外周血CD8+ T细胞和Jurkat细胞，CRISPR/Cas9基因编辑技术敲除CD8+ T、Jurkat细胞的TCR基因，制备过表达转基因TCR的重组慢病毒，在敲除内源性TCR的CD8+ T和Jurkat细胞中用慢病毒过表达转基因TCR制备TCR-T细胞，多色FCM检测TCR-T细胞中TCR和CD3的表达水平，荧光素酶活性实验检测TCR-T细胞对HPV16阳性SiHa细胞的杀伤效率。结果：CRIPSR/Cas9基因编辑技术高效地敲除了外周血CD8+ T细胞和Jurkat细胞中的TRAC和TRBC基因，敲除效率分别为（81.4±4.5）%、（98.5±0.07）%，制备的无内源TCR的TCR-T细胞高效表达转基因TCR，在外周血CD8+ T和Jurkat细胞中表达率为（66.0±17.8）%、（97.3±2.6）%，敲除内源TRAC和TRBC基因有效增强CD8+ T和Jurkat细胞膜表达转基因TCR（均P<0.01），敲除内源TCR增强TCR-T细胞特异性杀伤HPV16阳性的SiHa细胞[（71.4±1.0）% vs （35.1±2.0）%，P<0.01）]。结论：无内源TCR的TCR-T细胞显著增强转基因TCR的表达和对HPV16阳性宫颈癌SiHa细胞的靶向杀伤能力，为提高TCR-T细胞的临床疗效提供了实验依据。

Practice of Ethics Review on the First TCR-T Cell Therapy for Advanced Pancreatic Cancer / 中国医学伦理学

This paper retrospectively reported the ethical evaluation, discussion, review and decision made by the ethics committee of Peking University Shenzhen hospital on the first case study of TCR-T technology in the treatment of advanced pancreatic cancer. The issues discussed included the nature, risk-benefit assessment, informed consent and risk control of the case. Finally, three suggestions were put forward, including strengthen the supervision of innovative treatment research projects, implement full and effective informed consent by using doctor-patient joint decision-making mode, and improve the ability of ethical substance review, in order to provide reference for the ethics committee to review clinical research projects with cutting-edge technologies such as cell therapy.

Research progress on adoptive cell immunotherapy for breast cancer / 中国肿瘤生物治疗杂志

@#[摘 要] 目前国际上取得重大进展的四类过继性细胞免疫治疗（ACT）技术主要包括肿瘤浸润淋巴细胞（TIL）、CAR-T细胞、TCR-T细胞和CAR-NK细胞治疗。乳腺癌相关研究结果表明，TIL能预测乳腺癌的预后，间质TIL增加与良好的预后相关；CAR-T细胞免疫治疗在血液系统肿瘤治疗中取得巨大突破后，现已用于靶向实体肿瘤治疗，并在乳腺癌的治疗中开展了多种靶点的临床试验；TCR-T细胞疗法依赖于MHC，可以识别MHC分子呈递的任何抗原，具有更广泛的靶抗原，在治疗实体瘤方面更有前景，多项乳腺癌TCR-T细胞治疗临床试验正在进行中；CAR-NK细胞治疗是通过借鉴CAR-T细胞的结构而设计的，具有出色的抗肿瘤能力，比CAR-T细胞疗法更安全，可能将为肿瘤免疫治疗带来新的更大发展。ACT在乳腺癌的研究和临床应用领域仍具挑战，其中TIL疗法难以产生足量的特异性T细胞，CAR-T和CAR-NK细胞疗法均不同程度存在细胞的持久性、快速归巢到肿瘤床、毒性和转导效率等问题。尽管存在不足，但随着基因工程、肿瘤免疫学和分子生物学等多学科的迅速发展，相信ACT技术有望为乳腺癌患者治疗带来新的希望。

Caracterización del perfil de reordenamientos génicos de inmunoglobulinas y receptores de linfocitos T en leucemia linfoblástica aguda pediátrica / Pattern of immunoglobulins and T lymphocyte receptor gene rearrangements in childhood acute lymphoblastic leukemia / Caracterização do perfil de rearranjos gênicos de imunoglobulinas e receptores de linfócitos T na leucemia linfoide aguda pediátrica

Resumen Durante la ontogenia linfocitaria se produce el reordenamiento de los segmentos génicos V-(D)-J que codifican para la región variable de las cadenas de inmunoglobulinas (Ig) y receptores de linfocitos T (TCR). Durante este proceso, los segmentos se reordenan al azar y ocurren deleciones e inserciones de nucleótidos en la región de unión entre ellos. Los objetivos del presente trabajo fueron describir las incidencias de los reordenamientos Ig/TCR y de los segmentos V-(D)-J involucrados, en niños con leucemia linfoblástica aguda (LLA). Para ello se estudiaron 769 pacientes pediátricos con LLA, diagnosticados entre 1999 y 2018 por los centros de la Sociedad Argentina de Hemato-Oncología Pediátrica. Se caracterizaron reordenamientos de Ig/TCR mediante PCR-multiplex y secuenciación para la búsqueda de recombinaciones génicas IGH, IGK, TCRB, TCRG y TCRD, en muestras de ADN obtenidas de médula ósea o sangre periférica al diagnóstico. El 95% (n=730) de los casos presentaron reordenamientos Ig/TCR. En el 68% de los casos se caracterizaron recombinaciones génicas IGH, en 43% IGK, en 25% TCRB, en 49% TCRG y en el 55% TCRD. Se caracterizó un total de 2506 reordenamientos de Ig/TCR que correspondían 1161 a inmunoglobulinas y 1345 a TCR. En la mayoría de los casos los reordenamientos de IGH fueron completos, IGK involucró a IGKde, TRCB se reordenó frecuentemente con el segmento Jb2, TCRG involucró preferentemente a Vg9 y los TCRD fueron principalmente reordenamientos incompletos. Este trabajo constituye el primer estudio realizado en la Argentina sobre la caracterización de reordenamientos Ig/TCR en un número muy significativo de pacientes con LLA pediátrica.

Abstract During lymphocyte ontogeny, the variable region of immunoglobulin (Ig) and T-cell receptor (TCR) is generated by rearrangements of the V-(D)-J gene segments. In this random process, nucleotide deletions and insertions occur between V-(D)-J segments. The aims of this work were to describe the incidence of Ig/TCR rearrangements, and the V-(D)-J segments involved in acute lymphoblastic leukemia (ALL) patients. With this purpose, 769 pediatric ALL patients belonging to Sociedad Argentina de Hemato-Oncología Pediátrica, diagnosed between 1999 and 2018, were studied. Ig/TCR rearrangements were characterized by multiplex PCR and sequencing to evaluate IGH, IGK, TCRB, TCRG and TCRD rearrangements in DNA samples obtained at diagnosis from bone marrow or peripheral blood. In total, 95% (n=730) of patients disclosed Ig/TCR rearrangements. IGH rearrangements were detected in 68% of cases; in 43% IGK, in 25% TCRB, in 49% TCRG and in 55% of cases, TCRD. A total of 2506 Ig/TCR rearrangements were characterized, being 1161 immunoglobulins and 1345 TCR. In most cases, IGH rearrangements were complete, IGK involved IGKde, TRCB was frequently rearranged with the Jb2 segment, TCRG preferentially involved Vg9, and TCRDs were mostly incomplete rearrangements. This work is the first study of Ig/TCR rearrangements characterization in a very significant number of childhood ALL carried out in Argentina.

Resumo Durante a ontogenia dos linfócitos, ocorre um rearranjo dos segmentos gênicos V-(D)-J que codificam para a região variável das cadeias de imunoglobulinas (Ig) e receptores de linfócitos T (TCR). Durante esse processo, os segmentos reorganizam-se aleatoriamente e exclusões e inserções de nucleotídeos ocorrem na região da união entre eles. Os objetivos do presente trabalho foram descrever as incidências dos rearranjos Ig/TCR e dos segmentos V-(D)-J envolvidos, em crianças com leucemia linfoide aguda (LLA). Para tanto, foram estudados 769 pacientes pediátricos com LLA, diagnosticados entre 1999 e 2018 pelos centros da Sociedade Argentina de Hemato-Oncologia Pediátrica. Rearranjos de Ig/TCR foram caracterizados através de PCR-multiplex e sequenciação para procurar recombinações gênicas IGH, IGK, TCRB, TCRG e TCRD em amostras de DNA obtidas da medula óssea ou sangue periférico no diagnóstico. Do total de pacientes estudados, 95% (n=730) apresentaram rearranjos de Ig/TCR. Os rearranjos gênicos IGH foram caracterizados em 68% dos casos, em 43% de IGK, em 25% de TCRB, em 49% de TCRG e em 55% de TCRD. Foi caracterizado um total de 2506 rearranjos de Ig/TCR, correspondendo 1161 a imunoglobulinas e 1345 a TCR. Na maioria dos casos, os rearranjos de IGH foram concluídos, o IGK envolveu o IGKde, o TRCB foi frequentemente rearranjado com o segmento Jb2, o TCRG preferencialmente envolveu o Vg9 e os TCRDs foram principalmente os rearranjos incompletos. Este trabalho constitui o primeiro estudo realizado na Argentina sobre a caracterização de rearranjos de Ig/TCR em um número muito significativo de pacientes com LLA pediátrica.

Higher-order assemblies in immune signaling: supramolecular complexes and phase separation

Signaling pathways in innate and adaptive immunity play vital roles in pathogen recognition and the functions of immune cells. Higher-order assemblies have recently emerged as a central principle that governs immune signaling and, by extension, cellular communication in general. There are mainly two types of higher-order assemblies: 1) ordered, solid-like large supramolecular complexes formed by stable and rigid protein-protein interactions, and 2) liquid-like phase-separated condensates formed by weaker and more dynamic intermolecular interactions. This review covers key examples of both types of higher-order assemblies in major immune pathways. By placing emphasis on the molecular structures of the examples provided, we discuss how their structural organization enables elegant mechanisms of signaling regulation.

Potentiating CD8

Metabolic regulation has been proven to play a critical role in T cell antitumor immunity. However, cholesterol metabolism as a key component of this regulation remains largely unexplored. Herein, we found that the low-density lipoprotein receptor (LDLR), which has been previously identified as a transporter for cholesterol, plays a pivotal role in regulating CD8

The perplexity and hope of adoptive T-cell therapy for soft tissue sarcoma / 中国肿瘤生物治疗杂志

@#[摘 要] 软组织肉瘤（soft tissue sarcoma, STS）是20岁以下人群恶性肿瘤死亡的5大原因之一，传统的治疗方法疗效不佳且患者耐受性差，而免疫治疗为攻克STS提供了新途径。STS细胞表面多种高免疫原性抗原可作为工程化T细胞的攻击靶点，过继细胞疗法（adoptive T-cell therapy，ACT）在STS中具有较大的应用潜力。靶向HER2的CAR-T细胞疗法和靶向NY-ESO-1的TCR-T细胞疗法分别在临床试验中产生了临床获益，但其疗效也受到肿瘤免疫微环境的影响。STS部分肿瘤抗原在正常组织也有表达，可被CAR-T或TCR-T细胞错误攻击而引起严重的毒副作用。为进一步增强ACT治疗STS的有效性和安全性，联合免疫检查点抑制剂的综合治疗、CAR-T设计中导入自杀基因等新治疗策略已进入STS的临床治疗。随着二代测序技术的进步，对STS各亚型免疫学性质有了更深入的研究，对免疫治疗在STS中的应用会更加“特异性”和“个体化”。

Current status and challenges of TCR-T therapy in solid tumor / 中国肿瘤生物治疗杂志

@#[Abstract] T cell receptors (TCR) are specifically expressed on T cell surface, which can recognize different tumor antigens to kill and scavenge cancerous cells. TCR-engineered T cells (TCR-T) therapy is to harbor TCR specific to tumor cells and modify the T cells with genetic engineering techniques to achieve the purpose of treating tumors after transfusion. Despite some achievements in TCR-T therapy, there are still some problems, such as treatment toxicity, limited T cell infiltration and antigen-specific deficiency and so on. So, the safety and effectiveness of TCR-T therapy need to be constantly optimized. Therefore，this paper summarizes the research status of TCR-T therapy for solid tumors in domestic and overseas, as well as the existing problems and countermeasures.

TCR immune repertoire characteristics of patients with drug-induced liver injury due to Polygonum multiflorum preparations / 中国中药杂志

To explore the immune status of patients with drug-induced liver injury caused by Polygonum multiflorum preparations,and analyze their immune characteristics. Case-control design was used to collect the cases of drug-induced liver injury caused by P. multiflorum preparations through key specialized surveillance. Five matching factors,namely type of P. multiflorum preparations,gender,age,basic diseases and concomitant medication were controlled. According to the ratio of 1 ∶ 1,cases of patients who took P. multiflorum preparations but with no liver injury were monitored at prospective hospitals. The demographic information,disease information,medication information and laboratory examination information of the two groups were recorded,and venous blood was collected. The gene sequence was detected by high-throughput sequencing technology,and the characteristics of TCR immune repertoire of the two groups were analyzed. A total of 46 pairs of patients were enrolled in the study. The results showed significant differences in the number of CDR3 and clone species,the length of amino acid sequence in CDR3 region,the abundance of V gene and J gene,the cross-linking of V-J gene and the diversity of immune repertoire between patients with drug-induced liver injury and patients without liver injury. The immunohistochemical diversity and high-frequency V-J cross-linking characteristics of patients with liver injury caused by P. multiflorum preparations were found,which provided a reference for screening out drug users to reduce the occurrence of liver injury caused by P. multiflorum preparations.

Characterization of Distinct T Cell Receptor Repertoires in Tumor and Distant Non-tumor Tissues from Lung Cancer Patients / 基因组蛋白质组与生物信息学报·英文版

T cells and T cell receptors (TCRs) play pivotal roles in adaptive immune responses against tumors. The development of next-generation sequencing technologies has enabled the analysis of the TCRβ repertoire usage. Given the scarce investigations on the TCR repertoire in lung cancer tissues, in this study, we analyzed TCRβ repertoires in lung cancer tissues and the matched distant non-tumor lung tissues (normal lung tissues) from 15 lung cancer patients. Based on our results, the general distribution of T cell clones was similar between cancer tissues and normal lung tissues; however, the proportion of highly expanded clones was significantly higher in normal lung tissues than in cancer tissues (0.021% ± 0.002% vs. 0.016% ± 0.001%, P = 0.0054, Wilcoxon signed rank test). In addition, a significantly higher TCR diversity was observed in cancer tissues than in normal lung tissues (431.37 ± 305.96 vs. 166.20 ± 101.58, P = 0.0075, Mann-Whitney U test). Moreover, younger patients had a significantly higher TCR diversity than older patients (640.7 ± 295.3 vs. 291.8 ± 233.6, P = 0.036, Mann-Whitney U test), and the higher TCR diversity in tumors was significantly associated with worse cancer outcomes. Thus, we provided a comprehensive comparison of the TCR repertoires between cancer tissues and matched normal lung tissues and demonstrated the presence of distinct T cell immune microenvironments in lung cancer patients.

High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells / 医学前沿

Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-γ and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.

Detection of peripheral CD14+CD277+monocyte-macrophage ratio with γδ TCR tetramer and analy-sis of its relationship with treatment outcome / 中华微生物学和免疫学杂志

Objective To investigate the role of peripheral CD14+monocyte-macrophages in the recognition of phosphorylated antigen by γδ T cells and its relationship with treatment outcome. Methods Three kinds of γδ TCR tetramers were used to stain PBMC collected from patients with tuberculosis ( TB) and neonatal umbilical cord blood samples. The proportions of various TB-specific antigen presenting cells (APC) in peripheral blood were analyzed, and their relationships with treatment outcome were assessed based upon clinical data. Results CD14+monocyte-macrophages both in tuberculosis patients′ peripheral blood and neonatal umbilical cord blood were the strongest binding cells to CD277 antibody and γδ TCR tet-ramers. The median (P50) of CD14+monocyte-macrophages reached the highest peak after taking anti-tu-berculosis treatment for about one month and patients′condition was improved obviously during this period. Conclusion This study elucidated that CD14+monocyte-macrophages accounted for the largest proportion of APC when γδ T cells recognized phosphorylated antigens, which provided reference data for further study on the mechanism of γδ T cells restrictively recognizing phosphorylated antigen and their significance in innate and adaptive immunity.

Recent advances in pMHC multimer technology / 中国免疫学杂志

To overcome the intrinsic low affinity between peptide bound major histocompatibility complex(pMHC) and T cell receptors (TCRs) on T cell surface,pMHC can be multimerized to enhance its avidity to TCRs.Since 20 years ago pMHC tetramer was first applied in the detection of antigen specific T cells,it has become one of the most important immunoassay tools.Recently,pMHC multimers have been significantly improved over the original tetramer.pMHC multimers with higher valence have been produced in order to enhance detection sensitivity.Additionally,reversible pMHC multimers,which can be released from T cell surface to avoid potential damage to T cells,also have been applied in the isolation of antigen specific T cells.As a class of molecular tools,pMHC multimers play an important role in immunoassays and immunotherapies.A good knowledge and effective utilization of those tools will be greatly helpful in scientific and clinical applications.

A brief introduction of identification of tumor antigen-specific TCR gene / 中国免疫学杂志

Adoptive therapy with T cells modified by tumor antigen specific T cell receptor(TCR)gene become a research hotspot in tumor biotherapy.The generation of high-affinity TCR is a significant pre-condition for TCR-T therapy.In this review,we focus on the identification of tumor antigen-specific TCR genes,which based on RT-PCR,single cell RT-PCR and CDR3 length polymorphism analysis.

T-cell receptor-engineered T cells for cancer treatment: current status and future directions

T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCR-engineered T cells began more than two decades ago, with numerous preclinical studies showing that such cells could mediate tumor lysis and eradication. The success of these trials provided the foundation for clinical trials, including recent clinical successes using TCR-engineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1). These successes demonstrate the potential of this approach to treat cancer. In this review, we provide a perspective on the current and future applications of TCR-engineered T cells for the treatment of cancer. Our summary focuses on TCR activation and both pre-clinical and clinical applications of TCR-engineered T cells. We also discuss how to enhance the function of TCR-engineered T cells and prolong their longevity in the tumor microenvironment.

Current situation and challenges of T cell receptor-engineered T cells in anti-tumor therapy / 中国肿瘤生物治疗杂志

@#T cell receptor-engineered T cell (TCR-T) therapy is one of the hotspots in the field of cancer immunotherapy. Considerable achievements have been made since the first successful clinical trial in 2006. However, problems still remain in cytotoxicity, safety and persistence of TCR-T therapy despite the rapid development. Improving the immunosuppressive tumor microenvironment and enhancingchemotaxis, infiltration as well as activation of TCR-T cell will be the key to improve its anti-tumor effect. Neoantigens, which are highly tumor-specific and immunogenic,are the basis for safe and effective treatment and individualized cancer immunotherapy. Besides, infusion of less differentiated T cell subsets is also a reliable way to generate a long-lasting immune response. Here, combing with current research progress, we offer our perspectives on the current situation and challenges of TCR-T from the three aspects above.

Applicability of PCR-based clonality assay in dogs with multicentric lymphoma / Aplicabilidade do ensaio de clonalidade por PCR em cães com linfoma multicêntrico

Linfoma multicêntrico apresenta alta prevalência dentre as neoplasias em cães, e o diagnóstico rotineiro não é eficaz para avaliação de prognóstico. A PCR para rearranjos de receptores de antígeno (PRRA) apresenta potencial para classificação e estadiamento de linfomas. Este trabalho objetiva relatar o desenvolvimento de um protocolo de PRRA para aplicação em cães, baseando-se em condições e primers descritos na literatura. Foram coletados aspirados de linfonodo de 10 cães com linfoma multicêntrico e 15 lâminas de linfonodo positivas para linfoma já secas ao ar, fixadas e coradas. O protocolo utilizado demonstrou-se eficaz na amplificação de DNA das amostras frescas e das lâminas, com sensibilidade de 75%, similar à de estudos anteriores. Resultados parciais sugerem prevalência de linfomas de células B (60%) sobre células T (40%). O presente estudo abre precedentes para uma série de novos estudos com diagnóstico molecular de linfomas.(AU)

Proliferación linfoide indolente cutánea CD8 positiva a propósito de tres casos con compromiso facial / Indolent CD8-positive t-cell lymphoid proliferation: on purpose three cases of facial commitment

Resumen La proliferación linfoide indolente cutánea CD8 positiva es una variante recientemente descrita de linfoma T cutáneo que se caracteriza por un nódulo, pápula o placa eritematosa de crecimiento lento que puede afectar la región facial o extrafacial. En el estudio de patología se caracteriza por un infiltrado monomorfo de linfocitosTalo largo de la dermis con presencia de zona de Grenz y ausencia de epidermotropismo. El infiltrado es característicamente CD8+ así como CD3+, TIA-1+, CD4-, CD56- CD30-, PD-1-, Granzima B- y EBER negativo. El índice de proliferación Ki-67 es inferior al 10% y se observan reordenamientos clonales de los genes del receptor de antígeno de la célula T, TCR. El seguimiento clínico es favorable y no se ha observado compromiso sistémico. Se presentan tres casos con compromiso facial (dos casos en pabellón auricular y un caso con compromiso nasal), con presentación clínica y hallaz gos histopatológicos típicos (curiosamente un caso con cambio de célula clara), y además se realizaron estudios de clonalidad.

Abstract Primary cutaneous indolent CD8-positive lymphoid proliferation is a recent variant of cutaneous T lymphoma that is characterized by nodule, papule or plaque erythematous with slow growth that can affect the facial or extrafacial region. In the histopathology study it is characterized by an infiltration of monomorphic T lymphocytes throughout the dermis with presence of Grenz zone and absence of epidermotropism. The infiltrate is characteristically CD 8+ and CD3+ TIA-1+ CD4-, CD56- CD30, PD-1, Granzyme B- and negative EBER. Ki-67 Proliferación linfoide indolente cutánea CD8 positiva a propósito de tres casos proliferation index is less than 10% and clonal T-cell receptor gene rearrangements. Clinical follow-up is favorable and has not been observed systemic involvement. We present three cases with facial involvement (two cases in ear and one case with nasal commitment) with typical clinical presentation, histopathological findings (curiously a case with clear cell change) and clonality studies.

T Cell's Sense of Self: a Role of Self-Recognition in Shaping Functional Competence of Naïve T Cells

Post-thymic naïve T cells constitute a key cellular arm of adaptive immunity, with a well-known characteristic of the specificity and robustness of responses to cognate foreign antigens which is presented as a form of antigen-derived peptides bound to major histocompatibility complex (MHC) molecules by antigen-presenting cells (APCs). In a steady state, however, these cells are resting, quiescent in their activity, but must keep full ranges of functional integrity to mount rapid and robust immunity to cope with various infectious pathogens at any time and space. Such unique property of resting naïve T cells is not acquired in a default manner but rather requires an active mechanism. Although our understanding of exactly how this process occurs and what factors are involved remains incomplete, a particular role of self-recognition by T cells has grown greatly in recent years. In this brief review, we discuss recent data on how the interaction of T cells with self-peptide MHC ligands regulates their functional responsiveness and propose that variable strength of self-reactivity imposes distinctly different levels of functional competence and heterogeneity.