抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

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The blockade of immune checkpoints in cancer immunotherapy

Regulatory T cells engage in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes. Little is known, however, about the molecular mechanism of their development. Here we show that Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells. Furthermore, retroviral gene transfer of Foxp3 converts naive T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+ regulatory T cells. Thus, Foxp3 is a key regulatory gene for the development of regulatory T cells.

/pdf/control-of-regulatory-t-cell-development-by-the-43sce116zb.pdf

Control of Regulatory T Cell Development by the Transcription Factor Foxp3

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T(H)) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (T(reg)) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T(reg) cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T(reg) cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.

Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.

Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.

/pdf/regulatory-t-cells-session-1-ws-045a-chairpersons-sayuri-4gomklbui7.pdf

Regulatory T cells session 1(WS-045a) Chairpersons: Sayuri Yamazaki, Steven Ziegler

Unusually, for a meeting held under the auspices of the Instituto Juan March de Estudios e Investigaciones (Madrid, Spain), this workshop took place at the Fundacao Calouste Gulbenkian in Lisbon, Portugal. It was held between 7 and 9 April 2003, and was organized by A. Coutinho, W. Haas and C. Martinez‐A. The meeting was co‐sponsored by the Instituto Gulbenkian de Ciencia and EMBO.

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This workshop gathered together 20 speakers and 26 participants to discuss recent progress in the understanding and management of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). SLE and RA are both remitting and relapsing systemic autoimmune diseases (AIDs), which are characterized by the production of pathological auto‐antibodies that participate in chronic inflammation and tissue destruction. Other AIDs include type 1 diabetes and multiple sclerosis (MS) and, like all these diseases, the prevalence of SLE and RA continues to increase in western countries. However, neither has a cure been found nor is their aetiology well understood. The challenge of this workshop was to bring together clinicians, geneticists and fundamental immunologists for a discussion‐orientated meeting. The subsequent reciprocal interactions provided a rare opportunity to integrate data from clinical and therapeutic perspectives with the molecular and cellular processes that form the basis of these diseases.

### First born, first line: innate immunity

The defective clearance of apoptotic cells has been shown in a number of human SLE‐like diseases that are associated with a mutation in the complement C1q gene. Whether similar defects are a general hallmark of SLE is often discussed, notably because this disease is characterized by the production of abnormally high titres of antibodies that bind to DNA and other nuclear molecules. K. Elkon (Seattle, WA, USA) reviewed recent progress in understanding the mechanisms that control the induction of apoptosis and the processing of dying cells (Kim et al ., 2003). Intriguingly, natural IgM antibodies …

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Keeping hopes high.

Regulatory t cells and immunological tolerance


 Forkhead box P3 (Foxp3)-positive intratumoral regulatory T (Treg) cells play critical roles in suppressing anti-tumor immune responses. It is reported that human tumors accumulate more Tregs than peripheral blood. However, it remains unclear whether intratumoral Tregs are primarily derived from Tregs in tumor-draining lymph nodes (dLNs) or are converted from conventional CD4+ T cells (Tconvs) in the transforming growth factor-beta -rich tumor microenvironment.Because each T-cell clone has its unique T-cell receptor (TCR), tracking the TCRs of the tumor Treg repertoire in the dLN Treg, dLN Tconv, and tumor Tconv enables us to identify the primary source of intratumoral Tregs. GFP+ hCD2+ CD25high and GFP- hCD2+ CD25int Tregs, which we defined as mature and immature Tregs, respectively, are distinguished from Tconvs in Foxp3-GDL Tg × Foxp3hCD2 Treg reporter mice having the Foxp3-GFP-diphtheria toxin receptor transgene and Foxp3-human CD2/CD52 knocked-in locus. On day 14 after subcutaneous injection of the Lewis lung carcinoma cell line, CD4+ Treg subsets and Tconvs in the tumor and dLN were collected for TCR sequencing, and the TCR repertoire overlap between these populations was quantified.We found that approximately 70%-80% of the Treg repertoire in the tumor overlapped with that in the dLN. Overlap between tumor Treg and tumor Tconv or dLN Tconv was at most 30% in tumor Tregs, significantly smaller than the tumor Treg-dLN Treg overlap. Moreover, single-cell TCR/RNA sequencing analysis exhibited that the tumor and dLN Treg clusters shared a significant number of T-cell clones, with few clones shared with tumor or dLN Tconv clusters. To examine whether dLN Tregs were the source of tumor Tregs even when they were actively repopulating, GFP+ mature Tregs were transiently depleted by administrating diphtheria toxin to tumor bearing mice. Mature tumor Tregs were completely depleted by day 2 and recovered rapidly through day 5 after DT administration. Analysis of the TCR repertoire of repopulated Treg and Tconv subsets revealed that repertoire overlap between tumor Treg and dLN or tumor Tconv was small and that tumor Treg-dLN Tregs overlap remained dominant, proposing that the repopulated intratumoral Tregs were also mainly derived from dLN Tregs. These results demonstrated that dLN-tumor mobilization was the primary source of intratumoral Tregs and that Tregs converted from Tconvs comprised only a small fraction of the intratumoral Tregs in our model. This finding suggests that Treg clones that suppress anti-tumor responses in the tumor also inhibit the priming of tumor-reactive T cells in the dLN, which can limit the efficacy of tumor site-specific Treg depletion therapy.
 Citation Format: Hiroyasu Aoki, Haruka Shimizu, Shigeyuki Shichino, Mikiya Tsunoda, Haru Ogiwara, Shohei Hori, Kouji Matsushima, Satoshi Ueha. Intratumoral regulatory T cell clones originate from the draining lymph nodes regulatory T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5630.

Abstract 5630: Intratumoral regulatory T cell clones originate from the draining lymph nodes regulatory T cells

A novel ILC2 subset was identified in the mouse intestine that constitutively expresses IL-4. Although the absence of the gut microbiota had marginal effects, feeding mice with a vitamin B1-deficient diet compromised the number of intestinal IL-4+ ILC2s.

Shohei Hori

Papers

Regulatory T cells session 1(WS-045a) Chairpersons: Sayuri Yamazaki, Steven Ziegler

Keeping hopes high.

Regulatory t cells and immunological tolerance

Abstract 5630: Intratumoral regulatory T cell clones originate from the draining lymph nodes regulatory T cells

Diet-mediated constitutive induction of novel IL-4+ ILC2 cells maintains intestinal homeostasis in mice