Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells.
We show here that the expression of 4-1BB is rapidly induced in γδ T cells following antigenic stimulation in both mice and humans, and ligation of the newly acquired 4-1BB with an agonistic anti-4-1BB augments cell division and cytokine production. We further demonstrate that γδ rather than αβ T cells protect mice from Listeria monocytogenes (LM) infection and 4-1BB stimulation enhances the γδ T-cell activities in the acute phase of LM infection. IFN-γ produced from γδ T cells was the major soluble factor regulating LM infection. Vγ1 + T cells were expanded in LM-infected mice and 4-1BB signal triggered an exclusive expansion of Vγ1 + T cells and induced IFN-γ in these Vγ1 + T cells. Similarly, 4-1BB was induced on human γδ T cells and shown to be fully functional. Combination treatment with human γδ T cells and anti-hu4-1BB effectively protected against LM infection in human γδ T cell-transferred NOD-SCID mice. Taken together, these data provide evidence that the 4-1BB signal is an important regulator of γδ T cells and induces robust host defense against LM infection.Keywords: 4-1BB r IFN-γ r Listeria monocytogenes r γδ T cells Introduction 4-1BB (CD137), a member of the TNFR superfamily, is an inducible T-cell costimulatory molecule [1][2][3]. With few exceptions, expression of 4-1BB is activation dependent. In fact, 4-1BB is not detected (<3%) on resting T cells or T-cell lines [4]. However, 4-1BB is stably upregulated when T cells are activated by a variety of agonists such as plate-bound anti-CD3, concanavalin A, phytohemagglutinin, interleukin (IL)-2, IL-4, and CD28, as well as phorbol myristic acetate and ionomycin, either in isolation or in combination with APCs [5,6]. Expression of 4-1BB has been reported on activated CD4 + T cells, CD8 + T cells, NK cells, and NKT cells, and in a constitutive manner on CD11c + dendritic cells (DCs) and CD4 + CD25 + Treg cells [1,3,[7][8][9]. Functional 4-1BB Correspondence: Dr. Byoung S. Kwon e-mail: bskwon@ncc.re.kr expression has also been observed on myeloid cells, including monocytes, neutrophils, mast cells, and eosinophils [10]. Once expressed, 4-1BB binds with a high affinity to 4-1BB ligand (4-1BBL) that is present on a variety of APCs such as DCs, B cells, and macrophages [1,4]. Stimulation of 4-1BB along with TCR engagement was shown to cause T-cell expansion, cytokine induction, and upregulation of anti-apoptotic genes, and to prevent activation-induced cell death [1][2][3]. The available data strongly suggest that 4-1BB is a bonafide CD8 + T-cell-activating molecule, although 4-1BB expression is comparable in CD4 + and CD8 + T cells. The differential effect of 4-1BB on CD4 + and CD8 + T cells is not completely understood [11][12][13].γδ T cells, a distinct lineage of T lymphocytes, represent 0.5-3% of all the T cells in the blood and secondary lymphoid organs [14,15]. γδ T cells constitute the major T lymphocyte population in mucosal tissues, where they play specific roles in the regulation of immune responses to many pathogens [16][17][18][19][20][21][22]...
Adoptive T cell therapy (ACT) requires lymphodepletion preconditioning to eliminate immune-suppressive elements and enable efficient engraftment of adoptively transferred tumor-reactive T cells. As anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells, the combination of anti-CD4 treatment and ACT has synergistic potential in cancer therapy. Here, we demonstrate a post-ACT conditioning regimen that involves transient anti-CD4 treatment (CD4post). Using murine melanoma, the combined effect of cyclophosphamide preconditioning (CTXpre), CD4post, and ex vivo primed tumor-reactive CD8+ T-cell infusion is presented. CTXpre/CD4post increases tumor suppression and host survival by accelerating the proliferation and differentiation of ex vivo primed CD8+ T cells and endogenous CD8+ T cells. Endogenous CD8+ T cells enhance effector profile and tumor-reactivity, indicating skewing of the TCR repertoire. Notably, enrichment of polyfunctional IL-18Rαhi CD8+ T cell subset is the key event in CTXpre/CD4post-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Rαhi subset is mediated by IL-18 signaling and TCR–MHC I interaction. This study highlights the clinical relevance of CD4post in ACT and provides insights regarding the immunological nature of anti-CD4 treatment, which enhances anti-tumor response of CD8+ T cells.
RELT (tumor necrosis factor receptor superfamily member 19-like, TNFRSF19L) is a TNFR superfamily member that is primarily expressed in immune cells and lymphoid tissues, but whose immunological function is not well-defined. Here, we show that RELT is expressed by naive T cells and DCs, and their activation or maturation decreases RELT expression. Using RELT knockout (RELT ) mice, we demonstrate that RELT deficiency selectively promotes the homeostatic proliferation of CD4 T cells but not CD8 T cells, and enhances anti-tumor CD8 T-cell responses. We also demonstrate, using an adoptive transfer model in which RELT is knocked-out in either the transferred transgenic CD8 T cells or the recipient melanoma-bearing mice, that RELT on multiple immune cells limits the hyper-response of tumor-specific CD8 T cells. Hyper-responsiveness of RELT-deficient T cells was induced by promoting their proliferation. Taken together, our findings suggest that RELT acts as a negative regulator that controls the early phase of T-cell activation probably by promoting T-cell apoptosis.
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