Aerobic glycolysis enables the effector differentiation potential of stem-like CD4^(+)T cells to combat cancer

In 1957,Macfarlane Burnet proposed the theory that harnessing the body’s immune system could be an effective method for cancer treatment[1].Today,T-cell-based immunotherapies have indeed become a vital part of cancer treatment[2].However,a deeper understanding of antitumor immunity is still necessary to further support these treatments.Notably,CD4^(+)T cells are central to mediating antitumor immune responses[3,4,5,6],yet the cellular and molecular programs governing CD4^(+)T-cell antitumor immunity remain unclear.Our recent research revealed that CD4^(+)T-cell immunity is critically dependent on an intrinsic stem-like program[7].

Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8^(+)T Cell Immunity against Tumor

T-cell-based immunotherapy is gaining momentum in cancer treatment;however,our comprehension of the transcriptional regulation governing T cell antitumor activity remains constrained.The objective of this study was to explore the function of interferon regulatory factor 4(IRF4)in antitumor CD8^(+)T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma model.To achieve this,we generated an Irf4^(GFP-DTR) mouse strain and discovered that CD8^(+)tumor-infiltrating lymphocytes(TILs)expressing high levels of IRF4.GFP exhibited a more differentiated PD-1high cell phenotype.By administering diphtheria toxin to tumor-bearing Irf4^(GFP-DTR) mice,we partially depleted IRF4.GFP^(+)TILs and observed an accelerated tumor growth.To specifically explore the function of IRF4 in antitumor CD8^(+)T cells,we conducted 3 adoptive cell therapy(ACT)models.Firstly,depleting IRF4.GFP^(+)CD8^(+)TILs derived from ACT significantly accelerated tumor growth,emphasizing their crucial role in controlling tumor progression.Secondly,deleting the Irf4 gene in antitumor CD8^(+)T cells used for ACT led to a reduction in the frequency and effector differentiation of CD8^(+)TILs,completely abolishing the antitumor effects of ACT.Lastly,we performed a temporal deletion of the Irf4 gene in antitumor CD8^(+)T cells during ACT,starting from 20 days after tumor implantation,which significantly compromised tumor control.Therefore,sustained expression of IRF4 is essential for maintaining CD8^(+)T cell immunity in the melanoma model,and these findings carry noteworthy implications for the advancement of more potent immunotherapies for solid tumors.

天然免疫细胞的获得性免疫属性及其在移植排斥中的作用

移植排斥反应涉及天然免疫细胞和获得性免疫细胞。几十年来,获得性免疫细胞一直是移植免疫研究主要方向。研究者发现天然免疫细胞具有令人惊讶的新特征,包括免疫记忆,这可能对进一步改善移植物存活具有重要意义。移植物在短期内的存活率非常好,但长期存活仍然较差,并且在临床上大多数移植物因慢性排斥而导致功能丢失(简称失功)。在动物模型和临床研究中,慢性排斥反应导致的移植物失功通常由天然免疫细胞主导,尤其是移植物中的巨噬细胞和自然杀伤细胞。最近的研究结果显示:天然免疫细胞可以表现出获得性免疫属性,其通过直接识别非己抗原,或在同种异体环境中被“训练”,从而表现出免疫记忆特征。在部分模型中,靶向这种天然免疫细胞获得性特征的治疗方法可以促进同种异体移植物长期存活。这些发现可能为促进临床移植物存活和恶性肿瘤以及自身免疫性疾病的治疗开辟新的治疗机会。笔者综合文献报道,介绍天然免疫细胞的获得性应答特征,通过充分讨论天然免疫细胞类型的异质性和可塑性,以及相关问题,激发研究者在该领域开展更多探索。

Transcriptional and epigenetic regulation of immune tolerance:roles of the NF-κB family members

Immune tolerance is a highly regulated state and involves diverse mechanisms.Central to the induction of tolerance is the targeted modulation of T-cell activities(both effector and regulatory),in which transcription factors play a significant role.The nuclear factor kappa-B(NF-κB)family is a family of transcription factors that not only are critically involved in diverse T-cell responses but also are regulated by many mechanisms to maintain tolerance and T-cell homeostasis.NF-κB,as a transcription factor,has been extensively studied in recent decades,and the molecular mechanisms that regulate NF-κB activities have been well documented.However,recent studies have revealed exciting new roles for NF-κB;in addition to its transcriptional activity,NF-κB can also activate diverse epigenetic mechanisms that mediate extensive chromatin remodeling of target genes to regulate T-cell activities.In this review article,we highlight recent discoveries and emerging opportunities in targeting NF-κB family members as well as their associated chromatin modifiers in the induction of immune tolerance and in the clinical treatment of immune diseases.

Role of CD8^(+) regulatory T cells in organ transplantation

CD8^(+)T cells are regulatory T cells(Tregs)that suppress both alloimmunity and autoimmunity in many animal models.This class of regulatory cells includes the CD8^(+)CD28^(-),CD8^(+)CD103^(+),CD8^(+)FoxP3^(+)and CD8^(+)CD122^(+)subsets.The mechanisms of action of these regulatory cells are not fully understood;however,the secretion of immunosuppressive cytokines,such as interleukin(IL)-4,IL-10 and transforming growth factor beta(TGF-β)as well as the direct killing of target cells via Fas L/Fas and the perforin/granzyme B pathways have been demonstrated in various models.Further studies are necessary to fully understand the mechanisms underlying the suppressive effects of Tregs and to provide experimental support for potential clinical trials.We recently observed that CD8^(+)CD122^(+)Tregs more potently suppressed allograft rejection compared to their CD4^(+)CD25^(+)counterparts,supporting the hypothesis that CD8^(+)Tregs may represent a new and promising Treg family that can be targeted to prevent allograft rejection in the clinic.In this review,we summarize the progress in the field during the past 7-10 years and discuss CD8^(+)Treg phenotypes,mechanisms of action,and their potential clinical applications;particularly in composite tissue transplants in burn and trauma patients.

The transcription factor RelB restrains group 2 innate lymphoid cells and type 2 immune pathology in vivo

The exact relationships between group 2 innate lymphoid cells(ILC2s)and Th2 cells in type 2 pathology,as well as the mechanisms that restrain the responses of these cells,remain poorly defined.Here we examined the roles of ILC2s and Th2 cells in type 2 lung pathology in vivo using germline and conditional fie/b-deficient mice.We found that mice with germline deletion of Relb^(-/-)spontaneously developed prominent type 2 pathology in the lung,which contrasted sharply with mice with T-cell-specific Relb deletion(Relb^(f/f)Cd4-Cre),which were healthy with no observed autoimmune pathology.We also found that in contrast to wild-type B6 mice,Rel6-defident mice showed markedly expanded ILC2s but not ILC1s or ILC3s.Moreover,adoptive transfer of naive CD4^(+)T cells into Rag1^(-/-)Relb^(-/-)hosts induced prominent type 2 lung pathology,which was inhibited by depletion of ILC2s.Mechanistically,we showed that Relb deletion led to enhanced expression of Bcl11b,a key transcription factor for ILC2s.We concluded that RelB plays a critical role in restraining ILC2s,primarily by suppressing Bcl11b activity,and consequently inhibits type 2 lung pathology in vivo.

Inhibitory Receptors of the Immune System:Functions and Therapeutic Implications

The immune system has a remarkable ability to respond to seemingly endless antigens.In essence,a productive immune response takes place along a well defined but treacherous line,that is to effectively eradicate pathogens,and at the same time avoid causing damage to self organs.This type of response is fine-tuned,at least in part,by a complex array of pathways that either promote or inhibit the activation of innate and adaptive immune cells.Much effort has been focused on pathways that can support immune activation.In this article,we review specifically pathways that can inhibit immune responses and maintain immune homeostasis,highlighting our recent understanding on the role of inhibitory receptors that selectively engage the self MHC class I molecules and the B7 superfamily members,we also discuss the inhibitory Fc receptors and inhibitory cytokines and how such pathways,either individually or collectively,regulate innate and adaptive immune responses.Finally,we summarize new emerging approaches on how such negative pathways can be therapeutically modulated in various disease settings.

The RNA helicase DHX15 is a critical regulator of natural killer-cell homeostasis and functions

The RNA helicase DHX15 is widely expressed in immune cells and traditionally thought to be an RNA splicing factor or a viral RNA sensor.However,the role of DHX15 in NK-cell activities has not been studied thus far.Here,we generated Dhx15-floxed mice and found that conditional deletion of Dhx15 in NK cells(Ncr1CreDhx15fl/fl mice)resulted in a marked reduction in NK cells in the periphery and that the remaining Dhx15-deleted NK cells failed to acquire a mature phenotype.As a result,Dhx15-deleted NK cells exhibited profound defects in their cytolytic functions.We also found that deletion of Dhx15 in NK cells abrogated their responsiveness to IL-15,which was associated with inhibition of IL-2/IL-15Rβ(CD122)expression and IL-15R signaling.The defects in Dhx15-deleted NK cells were rescued by ectopic expression of a constitutively active form of STAT5.Mechanistically,DHX15 did not affect CD122 mRNA splicing and stability in NK cells but instead facilitated the surface expression of CD122,likely through interaction with its 3′UTR,which was dependent on the ATPase domain of DHX15 rather than its splicing domain.Collectively,our data identify a key role for DHX15 in regulating NK-cell activities and provide novel mechanistic insights into how DHX15 regulates the IL-15 signaling pathway in NK cells.

New progress in immunobiology and transplantation research

In this special issue of Burns&Trauma,we focus on transplant immunology,highlighting the pressing issues in the field and emerging strategies in resolving these issues,especially in the area of tolerance induction.The ultimate goal is to achieve transplant tolerance,a state of stable transplant survival without lifelong immunosuppression.