BMB Reports 2023; 56(3): 140-144  https://doi.org/10.5483/BMBRep.2023-0014
CD4+ cytotoxic T cells: an emerging effector arm of anti-tumor immunity
Seongmin Jeong1,# , Nawon Jang1,# , Minchae Kim1 & Il-Kyu Choi1,2,*
1Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, 2New Biology Research Center (NBRC), Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
Correspondence to:

Tel: +82-53-785-1670; Fax: +82-53-785-1819; E-mail: ik_choi@dgist.ac.kr
#These authors contributed equally to this work.

Received: January 3, 2023; Revised: February 26, 2023; Accepted: February 26, 2023; Published online: March 7, 2023.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
While CD8+ cytotoxic T cells have long been considered the primary effector in controlling tumors, the involvement of CD4+ “helper” T cells in anti-tumor immunity has been underappreciated. The investigations of intra-tumoral T cells, fueled by the recent advances in genomic technologies, have led to a rethinking of the indirect role of CD4+ T cells that have traditionally been described as a “helper”. Accumulating evidence from preclinical and clinical studies indicates that CD4+ T cells can acquire intrinsic cytotoxic properties and directly kill various types of tumor cells in a major histocompatibility complex class II (MHC-II)-dependent manner, as opposed to the indirect “helper” function, thus underscoring a potentially critical contribution of CD4+ cytotoxic T cells to immune responses against a wide range of tumor types. Here, we discuss the biological properties of anti-tumor CD4+ T cells with cytotoxic capability and highlight the emerging observations suggesting their more significant role in anti-tumor immunity than previously appreciated.
Keywords: Anti-tumor immunity, Cancer immunotherapy, CD4+ cytotoxic T cells, CD4+ “helper” T cells, MHC-II antigen presentation
INTRODUCTION

In contrast to CD8+ T cells with direct cytotoxic effector function, CD4+ T cells have been shown to exhibit a diverse repertoire of indirect effector functions in response to numerous pathogenic challenges and environmental perturbations (1, 2). To perform these roles, naïve CD4+ T cells can differentiate into several functionally distinct effector T helper (TH) cell subsets, each of which in turn produces its signature cytokines that coordinate a particular TH effector program (e.g., TH1, TH2, and TH17); the differentiation is mainly directed by lineage-defining transcription factors, so-called master regulators. The best-defined TH subsets include TH1, TH2, TH17, follicular helper T cells (TFH), and T regulatory (Treg) cells, which need the expression of the master regulators T-bet, GATA-3, RORγt, BCL6, and FoxP3, respectively. Thus, CD4+ T cells are known to offer “help” to appropriate immune effectors in their specific roles as the primary orchestrators of a broad range of immune responses.

The recent successes in cancer immunotherapy, including immune checkpoint inhibitors and gene-modified T-cell therapies, have revolutionized the field of cancer therapy (3-5). These successes have led to intense research efforts to define key immune cell subsets and their effector mechanisms that are responsible for anti-tumor immune responses. The efforts have predominantly focused on CD8+ T cells because of their ability to directly engage and kill cancer cells expressing major histocompatibility complex class I (MHC-I) molecules. On the other hand, the role of CD4+ T cells in anti-tumor immunity has been underestimated, presumably due to their traditional view as “helpers” and the lack of major histocompatibility complex class II (MHC-II) expression in most types of cancer cells. However, a growing body of evidence indicates that some of the CD4+ T-cell populations can acquire cytotoxic effector programs and mediate direct tumor cell killing, a distinct from traditionally described “helper” function. Furthermore, although the MHC-II molecule is thought to be expressed primarily in specialized immune cells such as professional antigen-presenting cells (dendritic cells, B cells, and macrophages), it has become increasingly clear that a wide range of non-hematologic tumor cells can also express MHC-II molecules and present their endogenous tumor antigens to CD4+ T cells (6-18). These recent works underline the significant contribution of CD4+ cytotoxic T lymphocytes (CD4 CTLs) to potent tumor-specific immune responses and redirect attention toward their functional and therapeutic importance. Herein, we summarize the current understanding of the biology of CD4 CTLs, with particular emphasis on their important roles in anti-tumor immunity.

THE DIRECT CONTRIBUTION OF CD4 CTLS TO ANTI-TUMOR IMMUNITY

In addition to a traditional indirect role in offering immunologic help, a growing body of evidence highlights the importance of a direct cytolytic role for CD4+ T cells, especially in anti-tumor immunity. The first evidence came from preclinical studies in which the adaptive transfer of tumor-reactive CD4+ T cells into lymphopenic mice followed by CTLA-4 blockade resulted in the regression of large established melanomas; the anti-tumor efficacy of the T cells depends on their expression of cytotoxic effector molecules (granzyme B and perforin) and direct recognition of MHC-II molecules expressed in the tumor cells (19, 20). Subsequent studies showed that administration of OX40 or 4-1BB agonist antibody promotes the generation of CD4 CTLs and leads to a potent anti-tumor immune response in the context of cyclophosphamide-induced lymphopenia or therapeutic vaccination (using Flt3-ligand-expressing melanoma cells), respectively (21, 22). Moreover, a clinical study found NY-ESO-1-specific CD4+ T cells with cytotoxic phenotype after ipilimumab (CTLA-4 blockade) treatment in patients with advanced melanoma (23). These CD4+ T cells demonstrate the ability to kill autologous melanoma cells that naturally express the cognate tumor antigen in an MHC-II-restricted fashion, suggesting a direct involvement of CD4 CTLs in the clinical efficacy of CTLA-4 blockade.

Recent advances in omics technologies further shed light on the clinical relevance of CD4 CTLs in cancer. Single-cell RNA sequencing analyses of intra-tumoral immune cells revealed CD4+ T cells expressing cytotoxic molecules (granzymes, perforin, granulysin, and/or natural killer cell granule protein 7) in a broad range of cancer types, including solid tumors (head and neck cancer (24), breast cancer (25, 26), non-small-cell lung cancer (27), colorectal cancer (28), hepatocellular cancer (29, 30), bladder cancer (31), melanoma (7), neuroblastoma (32), and osteosarcoma (33) as well as hematologic malignancies (B-cell chronic lymphocytic leukemia (34), Burkitt’s lymphoma (35), and classical Hodgkin lymphoma (36). Some of these studies further illustrated that the identified CD4+ T-cell subsets displayed MHC-II-dependent direct cytotoxicity against patient tumor cells (37); more intriguingly, their presence was associated with a favorable prognosis (32) or clinical response to anti-PD-L1 therapy (7, 28, 31, 36) or therapeutic vaccination (38).

The therapeutic importance of CD4 CTLs also extends to chimeric antigen receptor (CAR) T-cell-based cancer immunotherapy. A recent study characterized long-term persisting CAR T cells in two patients with chronic lymphocytic leukemia who remained in complete remission more than ten years after infusion (39). Strikingly, the long-lasting CAR T cells were a functionally activated CD4+ cell population that exhibits cytolytic characteristics, implying that cytotoxic CD4+ CAR T cells are primarily responsible for long-term tumor control. This further underscores the crucial role of CD4 CTLs in the therapeutic efficacy of cancer immunotherapeutics widely used in the clinic.

GENERATION AND REGULATION OF CD4 CTLS

There are likely multiple layers of “differentiation pathways” that specify CD4 CTLs. Costimulatory signals (through OX40 (21), 4-1BB (22), and CD70 (40, 41), cytokine (IL-2) (42), class I-restricted T-cell-associated molecule (CRTAM) (43), and lymphopenic condition (19, 20) appear to be involved in the generation of CD4 CTL. In addition, a previous work in which low antigen dose was associated with preferential CD4 CTL differentiation suggested that at the priming phase, T-cell receptor signal strength may contribute to the acquisition of cytotoxic activity by CD4+ T cells (44). In parallel to these various extrinsic cues, CD4 CTLs are heterogeneous in their expression of transcription factors, such as Eomes, T-bet, Runx3, Blimp-1, and Hobit (alone or in combination thereof) (21, 42, 43, 45, 46), as opposed to other CD4+ T-cell subsets (TH1, TH2, TH17, TFH, and Treg), which are characterized by a single lineage-specifying transcription factor. It is conceivable that the basis for this transcriptional heterogeneity might rely upon distinct immunological microenvironments that the CD4 CTL populations were detected; they might be primed and/or regulated by different environmental cues (e.g., differences in secondary lymphoid tissues versus tumor tissues or those in the tumor microenvironment). However, this remains to be robustly investigated. Furthermore, it has been reported that certain well-defined TH subsets (TH2, TH9, TH17, and more frequently, TH1) can acquire cytotoxic capacity, suggesting their functional plasticity (46-49). Although it has been proposed that the CD4 CTL populations are derived from the parental TH subsets (50, 51), it still remains unclear whether they are intermediate subsets (in the transition to an ultimate fate) or mixed subsets with multi-functions (resulting from the conversion or undefined mechanisms). Taken together, these findings suggest that there are complex biologic features of CD4 CTLs across both cancer and other immune contexts, and this requires further study to better elucidate molecular mechanisms for their dynamic process with distinct microenvironmental cues in cancer-bearing hosts.

THE IMPLICATION OF CD4 CTLS IN CANCER IMMUNOTHERAPY

The recognition of the therapeutic potential of CD4 CTLs in cancer has spurred efforts to develop novel approaches that harness cytotoxic CD4+ T-cell immunity to tumors. A recent study opens up a new approach for CD4 CTL-based cancer immunotherapy (40, 41). This work revealed that the Epstein-Barr virus signaling protein LMP1 enables B cells (including tumor B cells) to function as a “unique antigen-presenting cell” that directly primes CD4 CTLs. By exploiting the LMP1 signaling, an innovative approach was then developed to generate therapeutic CD4 CTLs against B-cell cancers. The produced CD4 CTLs exerted a potent anti-tumor activity against pre-established syngeneic B-cell lymphomas; the therapeutic efficacy was further enhanced upon the combination with PD-1 checkpoint blockade, resulting in complete regression of the tumor in the majority of mice. These results offer a solid foundation for the application of CD4 CTLs in cancer immunotherapy and a strong rationale for a combination therapy with CD4 CTLs and checkpoint blockade.

Apart from direct cytotoxicity, a major subset of CD4 CTLs appears to possess helper functions through the secretion of effector cytokines, such as IFN-γ and TNF-α. These cytokines have been shown to exert not only anti-tumor activity (via inducing growth arrest of cancer cells and destroying the tumor vasculature) (52, 53) but also stimulate other anti-tumor immune effectors such as CD8+ T cells, natural killer cells, and macrophages in the tumor microenvironment (Fig. 1) (54-56). This MHC-II-independent mechanism may contribute to CD4 CTL-mediated anti-tumor immunity as another critical arm. Accordingly, CD4 CTLs have the therapeutic potential to control MHC-II-negative as well as MHC-II-positive cancers.

The MHC-II molecule is paramount for antigen presentation to CD4 CTLs, and their responses are thus dependent on the expression of MHC-II on target cells. Since this molecule is known to display a restricted tissue distribution, it has been believed that most tumor cells lack its expression and cannot be targeted by CD4 CTLs. However, MHC-II expression and antigen-presenting capabilities have been increasingly reported in diverse types of non-hematologic human tumors, including melanoma (6-8), breast cancer (9, 10), colorectal cancer (11, 12), ovarian cancer (13, 14), prostate cancer (15), glioma (17), bladder cancer (31), and non-small-cell lung cancer (18). Given that these solid tumors are derived from tissues that are normally incapable of presenting their endogenous antigens on MHC-II molecules, they could acquire the antigen-presenting capacity under specific contexts. Although MHC-II antigen presentation is known to be induced by IFN-γ in some tumor cells (57, 58), mechanisms for its induction and regulation in tumor cells largely remain unknown. Understanding these mechanisms will provide a basis for rational strategies to enhance MHC-II antigen presentation on otherwise negative tumor cells, converting them into targets of CD4 CTLs.

CONCLUDING REMARKS

CD4+ T cells were initially viewed as mere “helpers” with indirect roles in the immune system. The discovery of CD4+ T-cell subsets, which specialize to become cytolytic and exert direct cytotoxic effector functions, suggests their more significant role than previously thought. The recent preclinical and clinical data underline the critical roles of CD4 CTLs in anti-tumor immunity and therapeutic response to currently used cancer immunotherapeutics, such as checkpoint inhibitor therapy and CAR T-cell therapy. The emerging appreciation of the functional and therapeutic potential of CD4 CTLs should lead us to redefine our understanding of T-cell-mediated anti-tumor immunity and rethink the design of cancer immunotherapy. However, there remain knowledge gaps on the underlying mechanisms of how CD4 CTLs are generated and regulated in the distinct immunological microenvironments of cancer-bearing hosts and how MHC-II antigen presentation is induced in diverse cancer types. These novel biological insights will enable the development of novel immunotherapeutic strategies that exploit the unique capabilities of CD4 CTLs.

ACKNOWLEDGEMENTS

This work was supported by grants from the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant no. NRF-2022R1A2C109214511 to I.-K.C.) and the DGIST Start-up Fund Program of the Ministry of Science and ICT (grant no. 2023010020 to I.-K.C.).

CONFLICTS OF INTEREST

I.-K.C. has a patent about the use of EBV LMP1 cancer immunotherapy issued.

FIGURE
Fig. 1. MHC-Ⅱ-independent anti-tumor mechanisms of CD4+ cytotoxic T lymphocytes (CD4 CTLs). CD4 CTLs can secret effector cytokines, IFN-γ and TNF-α, that (1) induce senescence-associated growth arrest in tumor cells, (2) destruct tumor blood vessels, and (3) stimulate immune effector cells, such as CD8+ T cells (“CD8 T”), natural killer cells (“NK”), and macrophages (“Mø”), to kill tumor cells.
REFERENCES
  1. Zhou L, Chong MM and Littman DR (2009) Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646-655
    Pubmed CrossRef
  2. Zhu J, Yamane H and Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28, 445-489
    Pubmed KoreaMed CrossRef
  3. Zappasodi R, Merghoub T and Wolchok JD (2018) Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell 33, 581-598
    Pubmed KoreaMed CrossRef
  4. Barrett DM, Singh N, Porter DL, Grupp SA and June CH (2014) Chimeric antigen receptor therapy for cancer. Annu Rev Med 65, 333-347
    Pubmed KoreaMed CrossRef
  5. Ott PA, Hodi FS, Kaufman HL, Wigginton JM and Wolchok JD (2017) Combination immunotherapy: a road map. J Immunother Cancer 5, 16
    Pubmed KoreaMed CrossRef
  6. Johnson DB, Estrada MV, Salgado R et al (2016) Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun 7, 10582
    Pubmed KoreaMed CrossRef
  7. Rodig SJ, Gusenleitner D, Jackson DG et al (2018) MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci Transl Med 10, eaar3342
    Pubmed CrossRef
  8. Johnson DB, Bordeaux J, Kim JY et al (2018) Quantitative spatial profiling of PD-1/PD-L1 interaction and HLA-DR/IDO-1 predicts improved outcomes of anti-PD-1 therapies in metastatic melanoma. Clin Cancer Res 24, 5250-5260
    Pubmed KoreaMed CrossRef
  9. Park IA, Hwang SH, Song IH et al (2017) Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling. PLoS One 12, e0182786
    Pubmed KoreaMed CrossRef
  10. Loi S, Dushyanthen S, Beavis PA et al (2016) RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res 22, 1499-1509
    Pubmed KoreaMed CrossRef
  11. Michel S, Linnebacher M, Alcaniz J et al (2010) Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes. Int J Cancer 127, 889-898
    Pubmed KoreaMed CrossRef
  12. Bustin SA, Li SR, Phillips S and Dorudi S (2001) Expression of HLA class II in colorectal cancer: evidence for enhanced immunogenicity of microsatellite-instability-positive tumours. Tumour Biol 22, 294-298
    Pubmed CrossRef
  13. Callahan MJ, Nagymanyoki Z, Bonome T et al (2008) Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer. Clin Cancer Res 14, 7667-7673
    Pubmed KoreaMed CrossRef
  14. Turner TB, Meza-Perez S, Londono A et al (2017) Epigenetic modifiers upregulate MHC II and impede ovarian cancer tumor growth. Oncotarget 8, 44159-44170
    Pubmed KoreaMed CrossRef
  15. Younger AR, Amria S, Jeffrey WA et al (2008) HLA class II antigen presentation by prostate cancer cells. Prostate Cancer Prostatic Dis 11, 334-341
    Pubmed CrossRef
  16. Roemer MGM, Redd RA, Cader FZ et al (2018) Major histocompatibility complex class ii and programmed death ligand 1 expression predict outcome after programmed death 1 blockade in classic hodgkin lymphoma. J Clin Oncol 36, 942-950
    Pubmed KoreaMed CrossRef
  17. Soos JM, Krieger JI, Stuve O et al (2001) Malignant glioma cells use MHC class II transactivator (CIITA) promoters III and IV to direct IFN-gamma-inducible CIITA expression and can function as nonprofessional antigen presenting cells in endocytic processing and CD4(+) T-cell activation. Glia 36, 391-405
    Pubmed CrossRef
  18. Yazawa T, Kamma H, Fujiwara M et al (1999) Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer. J Pathol 187, 191-199
    Pubmed CrossRef
  19. Quezada SA, Simpson TR, Peggs KS et al (2010) Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med 207, 637-650
    Pubmed KoreaMed CrossRef
  20. Xie Y, Akpinarli A, Maris C et al (2010) Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma. J Exp Med 207, 651-667
    Pubmed KoreaMed CrossRef
  21. Hirschhorn-Cymerman D, Budhu S, Kitano S et al (2012) Induction of tumoricidal function in CD4+ T cells is associated with concomitant memory and terminally differentiated phenotype. J Exp Med 209, 2113-2126
    Pubmed KoreaMed CrossRef
  22. Curran MA, Geiger TL, Montalvo W et al (2013) Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin. J Exp Med 210, 743-755
    Pubmed KoreaMed CrossRef
  23. Kitano S, Tsuji T, Liu C et al (2013) Enhancement of tumor-reactive cytotoxic CD4+ T cell responses after ipilimumab treatment in four advanced melanoma patients. Cancer Immunol Res 1, 235-244
    Pubmed KoreaMed CrossRef
  24. Puram SV, Tirosh I, Parikh AS et al (2017) Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171, 1611-1624
    Pubmed KoreaMed CrossRef
  25. Azizi E, Carr AJ, Plitas G et al (2018) Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174, 1293-1308
    Pubmed KoreaMed CrossRef
  26. Zhang Y, Chen H, Mo H et al (2021) Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer. Cancer Cell 39, 1578-1593
    Pubmed CrossRef
  27. Guo X, Zhang Y, Zheng L et al (2018) Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat Med 24, 978-985
    Pubmed CrossRef
  28. Zhang L, Yu X, Zheng L et al (2018) Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature 564, 268-272
    Pubmed CrossRef
  29. Zhang Q, He Y, Luo N et al (2019) Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 179, 829-845
    Pubmed CrossRef
  30. Zheng C, Zheng L, Yoo JK et al (2017) Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342-1356
    Pubmed CrossRef
  31. Oh DY, Kwek SS, Raju SS et al (2020) Intratumoral CD4(+) T cells mediate anti-tumor cytotoxicity in human bladder cancer. Cell 181, 1612-1625
    Pubmed KoreaMed CrossRef
  32. Tang XX, Shimada H and Ikegaki N (2021) Clinical relevance of CD4 cytotoxic T cells in high-risk neuroblastoma. Front Immunol 12, 650427
    Pubmed KoreaMed CrossRef
  33. Zhou Y, Yang D, Yang Q et al (2020) Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma. Nat Commun 11, 6322
    Pubmed KoreaMed CrossRef
  34. Porakishvili N, Kardava L, Jewell AP et al (2004) Cytotoxic CD4+ T cells in patients with B cell chronic lymphocytic leukemia kill via a perforin-mediated pathway. Haematologica 89, 435-443
  35. Khanna R, Burrows SR, Thomson SA et al (1997) Class I processing-defective Burkitt's lymphoma cells are recognized efficiently by CD4+ EBV-specific CTLs. J Immunol 158, 3619-3625
    Pubmed CrossRef
  36. Cader FZ, Hu X, Goh WL et al (2020) A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma. Nat Med 26, 1468-1479
    Pubmed KoreaMed CrossRef
  37. Cachot A, Bilous M, Liu YC et al (2021) Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer. Sci Adv 7, eabe3348
    Pubmed KoreaMed CrossRef
  38. Hu Z, Leet DE, Allesoe RL et al (2021) Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma. Nat Med 27, 515-525
    Pubmed KoreaMed CrossRef
  39. Melenhorst JJ, Chen GM, Wang M et al (2022) Decade-long leukaemia remissions with persistence of CD4(+) CAR T cells. Nature 602, 503-509
    Pubmed KoreaMed CrossRef
  40. Choi IK, Wang Z, Ke Q et al (2018) Signaling by the Epstein-Barr virus LMP1 protein induces potent cytotoxic CD4(+) and CD8(+) T cell responses. Proc Natl Acad Sci U S A 115, E686-E695
    Pubmed KoreaMed CrossRef
  41. Choi IK, Wang Z, Ke Q et al (2021) Mechanism of EBV inducing anti-tumour immunity and its therapeutic use. Nature 590, 157-162
    Pubmed KoreaMed CrossRef
  42. Sledzinska A, Vila de Mucha M, Bergerhoff K et al (2020) Regulatory T cells restrain interleukin-2- and blimp-1-dependent acquisition of cytotoxic function by CD4(+) T cells. Immunity 52, 151-166
    Pubmed KoreaMed CrossRef
  43. Takeuchi A, Badr Mel S, Miyauchi K et al (2016) CRTAM determines the CD4+ cytotoxic T lymphocyte lineage. J Exp Med 213, 123-138
    Pubmed KoreaMed CrossRef
  44. Brown DM, Kamperschroer C, Dilzer AM, Roberts DM and Swain SL (2009) IL-2 and antigen dose differentially regulate perforin- and FasL-mediated cytolytic activity in antigen specific CD4+ T cells. Cell Immunol 257, 69-79
    Pubmed KoreaMed CrossRef
  45. Cruz-Guilloty F, Pipkin ME, Djuretic IM et al (2009) Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med 206, 51-59
    Pubmed KoreaMed CrossRef
  46. Serroukh Y, Gu-Trantien C, Hooshiar Kashani B et al (2018) The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes. Elife 7, e30496
    Pubmed KoreaMed CrossRef
  47. Lancki DW, Hsieh CS and Fitch FW (1991) Mechanisms of lysis by cytotoxic T lymphocyte clones. Lytic activity and gene expression in cloned antigen-specific CD4+ and CD8+ T lymphocytes. J Immunol 146, 3242-3249
    Pubmed CrossRef
  48. Akhmetzyanova I, Zelinskyy G, Littwitz-Salomon E et al (2016) CD137 agonist therapy can reprogram regulatory T cells into cytotoxic CD4+ T cells with antitumor activity. J Immunol 196, 484-492
    Pubmed CrossRef
  49. Appay V, Zaunders JJ, Papagno L et al (2002) Characterization of CD4(+) CTLs ex vivo. J Immunol 168, 5954-5958
    Pubmed CrossRef
  50. Takeuchi A and Saito T (2017) CD4 CTL, a cytotoxic subset of CD4(+) T cells, their differentiation and function. Front Immunol 8, 194
    Pubmed KoreaMed CrossRef
  51. Waight JD, Chand D, Dietrich S et al (2018) Selective fcgammar co-engagement on APCs modulates the activity of therapeutic antibodies targeting T cell antigens. Cancer Cell 33, 1033-1047
    Pubmed KoreaMed CrossRef
  52. Braumuller H, Wieder T, Brenner E et al (2013) T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361-365
    Pubmed CrossRef
  53. Kammertoens T, Friese C, Arina A et al (2017) Tumour ischaemia by interferon-gamma resembles physiological blood vessel regression. Nature 545, 98-102
    Pubmed KoreaMed CrossRef
  54. Corthay A, Skovseth DK, Lundin KU et al (2005) Primary antitumor immune response mediated by CD4+ T cells. Immunity 22, 371-383
    Pubmed CrossRef
  55. Kennedy R and Celis E (2008) Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev 222, 129-144
    Pubmed CrossRef
  56. Haabeth OAW, Hennig K, Fauskanger M, Loset GA, Bogen B and Tveita A (2020) CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages. Blood Adv 4, 2595-2605
    Pubmed KoreaMed CrossRef
  57. Steimle V, Siegrist CA, Mottet A, Lisowska-Grospierre B and Mach B (1994) Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science 265, 106-109
    Pubmed CrossRef
  58. Neefjes J, Jongsma ML, Paul P and Bakke O (2011) Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 11, 823-836
    Pubmed CrossRef


This Article


Cited By Articles
  • CrossRef (0)

Author ORCID Information

Funding Information

Collections

Services
Social Network Service

e-submission

Archives