BCL6 is required for differentiation of Ig-like transcript 3-Fc-induced CD8+ T suppressor cells.
Chang Chih-Chao,Vlad George,D'Agati Vivette D,Liu Zhuoru,Zhang Qing-yin,Witkowski Piotr,Torkamani Ali A,Stokes Michael B,Ho Eric K,Cortesini Raffaello,Suciu-Foca Nicole
Journal of immunology (Baltimore, Md. : 1950)
Ig-like transcript 3 (ILT3) is an inhibitory receptor expressed by tolerogenic dendritic cells. When human CD8(+) T cells are allostimulated in the presence of recombinant ILT3-Fc protein, they differentiate into antigenic specific T suppressor (Ts) cells that inhibit CD4 and CD8 T cell effector function both in vitro and in vivo. ILT3-Fc-induced CD8(+) Ts cells express high amounts of BCL6 that are crucial to their function. Knockdown of BCL6 from unprimed human T cells prevents their differentiation into Ts cells, whereas ex vivo overexpression of BCL6 converts CD8(+) T cells into Ts cells. NOD/SCID mice transplanted with human pancreatic islets and humanized by injection of human PBMCs tolerate the graft and develop BCL6(high) CD8(+) Ts cells when treated with ILT3-Fc before or after the onset of rejection. This indicates that ILT3-Fc acts through BCL6 and is a potent immunosuppressive agent for reversing the onset of allo- or possibly autoimmune attacks against pancreatic islets.
10.4049/jimmunol.1001732
Cutting Edge: Transcription Factor BCL6 Is Required for the Generation, but Not Maintenance, of Memory CD8 T Cells in Acute Viral Infection.
Liu Zhenyu,Guo Yanyan,Tang Shupei,Zhou Lan,Huang Chunji,Cao Yi,Huang Huang,Wu Xiaoping,Meng Dongwei,Ye Lilin,He Haiyang,Xie Zhunyi,Wu Yuzhang,Liu Xindong,Zhou Xinyuan
Journal of immunology (Baltimore, Md. : 1950)
The differentiation of memory CD8 T cells is critical to the long-term cellular immunity. The transcription factor BCL6 has been reportedly important for the generation and maintenance of memory CD8 T cells; however, using the newly established BCL6 conditional knockout mouse model, we demonstrate that BCL6 is dispensable for the maintenance of established memory CD8 T cell pool, although BCL6 is still required for the generation of CD8 memory precursors upon acute viral infection. In addition, BCL6 promotes the expression of TCF-1 via directly binding to the (gene symbol for TCF-1) allele in CD8 memory precursors and forced expression of TCF-1 restores the generation of BCL6-deficient memory precursors. Thus, our findings clarify that BCL6 is dispensable for the maintenance of memory CD8 T cells, but functions as an important upstream of TCF-1 to regulate the generation of memory precursors in acute viral infection.
10.4049/jimmunol.1900014
Bcl6 controls granzyme B expression in effector CD8+ T cells.
Yoshida Kazuki,Sakamoto Akemi,Yamashita Kimihiro,Arguni Eggi,Horigome Satoshi,Arima Masafumi,Hatano Masahiko,Seki Naohiko,Ichikawa Tomohiko,Tokuhisa Takeshi
European journal of immunology
Bcl6, a sequence-specific transcriptional repressor, is important for generation and maintenance of memory CD8(+) T cells. Although memory CD8(+) T cells are generated from effector CD8(+) T cells, a role for Bcl6 in effector CD8(+) T cells is largely unknown. We show here that Bcl6 expression was transiently induced in activated CD8(+) T cells and continuously up-regulated in effector CD8(+) T cells. The amount of granzyme B mRNA among effector molecules produced by effector CD8(+) T cells inversely correlated with the amount of Bcl6 mRNA in CD8(+) T cells. Overexpression of Bcl6 in CD8(+) T cells resulted in lower killing activity at their effector phase, supporting the reduction of granzyme B expression in effector CD8(+) T cells by Bcl6. We identified a putative Bcl6-binding DNA sequence in the promoter region of the granzyme B gene. Binding of Bcl6 to the Bcl6-binding sequence was detected in naive CD8(+) T cells but not in activated CD8(+) T cells by chromatin immunoprecipitation assay. Furthermore, the Bcl6-binding sequence was required for Bcl6 to repress the luciferase reporter gene expression controlled by the granzyme B promoter. Thus, the granzyme B gene is a molecular target of Bcl6 in effector CD8(+) T cells.
10.1002/eji.200636165
Atypical BCL6/GATA3+ Primary Cutaneous Acral CD8-Positive T-Cell Lymphoma: A Diagnostic Challenge.
Prieto-Torres Lucia,Camacho-García Diana,Piris Miguel Ángel,Requena Luis,Rodríguez-Pinilla Socorro María
The American Journal of dermatopathology
ABSTRACT:Primary cutaneous acral CD8-positive T-cell lymphoma consists of slow-growing nodules in acral sites with a histopathology, suggesting high-grade lymphoma despite the indolent clinical course. It has been recently included in WHO-EORTC classification for primary cutaneous lymphomas as a provisional entity. A correct diagnosis of this entity is important because its differential diagnosis include more aggressive cutaneous lymphomas. We present a 53-year-old woman with an indolent solitary nodule on her right leg, which histopathologically showed features of CD8-positive T-cell lymphoma, although with some peculiarities, including epidermotropism, absence of CD68 expression, and positivity for GATA3 and Bcl6 in neoplastic cells. This case could contribute to better define the spectrum of this rare cutaneous lymphoma.
10.1097/DAD.0000000000001737
Programmed death 1 expressing CD8 CXCR5 follicular T cells constitute effector rather than exhaustive phenotype in patients with chronic hepatitis B.
Hepatology (Baltimore, Md.)
BACKGROUND AND AIMS:Classical CD8 T cells are implicated for protective and pathogenic roles in chronic hepatitis B (CHB) infection. Recently, a subset of CD8 T cells expressing C-X-C chemokine receptor type 5 (CXCR5) and exhibiting features of T cells has been identified during chronic viral infections. However, in CHB, knowledge of their roles is limited. APPROACH AND RESULTS:We characterized circulating CD8 CXCR5 cells and investigated their association with clinical and viral factors. We found that CHB infection did not influence the overall frequencies of CD8 CXCR5 cells whereas CD8 CXCR5 cells were increased. However, among CHB, CD8 CXCR5 cells were higher in patients with low HBsAg and HBV-DNA levels, patients who were HBeAg negative and had high fibrosis scores, and these cells exhibited a significant association with HBsAg and HBV-DNA reduction. Contrarily, CD8 CXCR5 cells were expanded and positively correlated with patients having high HBsAg, HBV-DNA, and alanine aminotransferase levels. CD8 CXCR5 cells express costimulatory molecules ICOS, OX40, CD40 ligand, inhibitory molecule programmed death 1, transcription factors B-cell lymphoma (BCL)-2, BCL-6, and signal transducer and activator of transcription 3, and are enriched in effector and central memory phenotype. Moreover, these cells are heterogeneous in nature given that they constitute different subsets of cytotoxic follicular T cells (TCF), including TCF1, TCF2, TCF17, and TCF22. Despite expressing high PD-1, CD8 CXCR5 cells are activated, proliferating, secreting more IFN-γ, IL-21, and IL-22, and have better cytolytic potential than CD8 CXCR5 cells, which were inhibited after PD-1/PD-L1 blockade. CD8 CXCR5 cells are efficient in helping B cells in terms of plasmablasts and plasma cell generation. CONCLUSIONS:In conclusion, CD8 CXCR5 cells are enriched in effector phenotypes, produce HBV-specific cytokines despite increased PD-1, and are associated with HBsAg and HBV-DNA reduction. These cells competently support B-cell function, required for viral clearance, which may serve as potential therapeutic targets for CHB.
10.1002/hep.32210
The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness.
Wu Tuoqi,Ji Yun,Moseman E Ashley,Xu Haifeng C,Manglani Monica,Kirby Martha,Anderson Stacie M,Handon Robin,Kenyon Elizabeth,Elkahloun Abdel,Wu Weiwei,Lang Philipp A,Gattinoni Luca,McGavern Dorian B,Schwartzberg Pamela L
Science immunology
During chronic viral infections and in cancer, T cells become dysfunctional, a state known as T cell exhaustion. Although it is well recognized that memory CD8 T cells account for the persistence of CD8 T cell immunity after acute infection, how exhausted T cells persist remains less clear. Using chronic infection with lymphocytic choriomeningitis virus clone 13 and tumor samples, we demonstrate that CD8 T cells differentiate into a less exhausted TCF1 and a more exhausted TCF1 population. Virus-specific TCF1 CD8 T cells, which resemble T follicular helper (T) cells, persist and recall better than do TCF1 cells and act as progenitor cells to replenish TCF1 cells. We show that TCF1 is both necessary and sufficient to support this progenitor-like CD8 subset, whereas cell-intrinsic type I interferon signaling suppresses their differentiation. Accordingly, cell-intrinsic TCF1 deficiency led to a loss of these progenitor CD8 T cells, sharp contraction of virus-specific T cells, and uncontrolled viremia. Mechanistically, TCF1 repressed several pro-exhaustion factors and induced Bcl6 in CD8 T cells, which promoted the progenitor fate. We propose that the TCF1-Bcl6 axis counteracts type I interferon to repress T cell exhaustion and maintain T cell stemness, which is critical for persistent antiviral CD8 T cell responses in chronic infection. These findings provide insight into the requirements for persistence of T cell immune responses in the face of exhaustion and suggest mechanisms by which effective T cell-mediated immunity may be enhanced during chronic infections and cancer.
10.1126/sciimmunol.aai8593
Tissue-resident CD4 T helper cells assist the development of protective respiratory B and CD8 T cell memory responses.
Son Young Min,Cheon In Su,Wu Yue,Li Chaofan,Wang Zheng,Gao Xiaochen,Chen Yao,Takahashi Yoshimasa,Fu Yang-Xin,Dent Alexander L,Kaplan Mark H,Taylor Justin J,Cui Weiguo,Sun Jie
Science immunology
Much remains unknown about the roles of CD4 T helper cells in shaping localized memory B cell and CD8 T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8 T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and T cells, and we have termed these cells as resident helper T (T) cells. Optimal T cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that T cells deliver local help to CD8 T cells through IL-21-dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8 T cell responses.
10.1126/sciimmunol.abb6852
CD8 Follicular T Cells Promote B Cell Antibody Class Switch in Autoimmune Disease.
Journal of immunology (Baltimore, Md. : 1950)
CD8 T cells can play both a protective and pathogenic role in inflammation and autoimmune development. Recent studies have highlighted the ability of CD8 T cells to function as T follicular helper (Tfh) cells in the germinal center in the context of infection. However, whether this phenomenon occurs in autoimmunity and contributes to autoimmune pathogenesis is largely unexplored. In this study, we show that CD8 T cells acquire a CD4 Tfh profile in the absence of functional regulatory T cells in both the IL-2-deficient and scurfy mouse models. Depletion of CD8 T cells mitigates autoimmune pathogenesis in IL-2-deficient mice. CD8 T cells express the B cell follicle-localizing chemokine receptor CXCR5, a principal Tfh transcription factor Bcl6, and the Tfh effector cytokine IL-21. CD8 T cells localize to the B cell follicle, express B cell costimulatory proteins, and promote B cell differentiation and Ab isotype class switching. These data reveal a novel contribution of autoreactive CD8 T cells to autoimmune disease, in part, through CD4 follicular-like differentiation and functionality.
10.4049/jimmunol.1701079