Intestinal lamina propria (LP) CD4 T cells play critical roles in maintaining intestinal homeostasis and in immune responses to enteric microbes, yet little is known regarding whether they contribute to age-associated intestinal immune dysfunction. In this study, we evaluated the direct ex vivo frequency, activation/inhibitory phenotype, death profiles, and in vitro functional responses of human jejunum LP CD4 T cells, including Th1, Th17, and Th22 subsets isolated from younger (<45 years) and older (>65years) persons. Expression of the co-inhibitory molecule CTLA-4 was significantly lower in older CD4 T cells, whereas expression of HLA-DR, CD38, CD57, and PD-1 were not significantly different between groups. Total CD4 T cell frequencies were similar between age groups, but lower frequencies and numbers of Th17 cells were observed directly ex vivo in older samples. Older Th17 and Th1 cells proliferated to a lesser degree following in vitro exposure to bacterial antigens vs. their younger counterparts. Levels of spontaneous cell death were increased in older CD4 T cells; however, cellular death profiles following activation did not differ based on age. Thus, small intestinal CD4 T cells from older persons have altered phenotypic and functional profiles including reduced expression of a co-inhibitory molecule, increased spontaneous cell death, and both reduced frequencies and altered functional responses of specific Th cell subsets. These changes may contribute to altered intestinal homeostasis and loss of protective gut immunity with aging.
Monocyte-derived dendritic cell (moDC)-based cancer therapies intended to elicit antitumor T-cell responses have limited efficacy in most clinical trials. However, potent and sustained antitumor activity in a limited number of patients highlights the therapeutic potential of moDCs. In vitro culture conditions used to generate moDCs can be inconsistent, and moDCs generated in vitro are less effective than natural DCs. Based on our study highlighting the ability for certain kinase inhibitors to enhance tumor antigenicity, we therefore screened kinase inhibitors for their ability to improve DC immunogenicity. We identified AKT inhibitor MK2206, DNA-PK inhibitor NU7441, and MEK inhibitor trametinib as the compounds most effective at modulating moDC immunogenicity. The combination of these drugs, referred to as MKNUTRA, enhanced moDC activity over treatment with individual drugs while exhibiting minimal toxicity. An evaluation of 335 activation and T-cell suppressive surface proteins on moDCs revealed that MKNUTRA treatment more effectively matured cells and reduced the expression of tolerogenic proteins as compared with control moDCs. MKNUTRA treatment imparted to ICT107, a glioblastoma (GBM) DC-based vaccine that has completed Phase II trials, an increased ability to stimulate patient-derived autologous CD8 + T cells against the brain tumor antigens IL13Rα2 (345-354) and TRP2 (180-188) . In vivo, treating ICT107 with MKNUTRA, prior to injection into mice with an established GBM tumor, reduced tumor growth kinetics. This response was associated with an increased frequency of tumor-reactive lymphocytes within tumors and in peripheral tissues. These studies broaden the application of targeted anticancer drugs and highlight their ability to increase moDC immunogenicity.
Background The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Results Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Conclusions Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.
Chronic HIV-1 infection results in the sustained disruption of gut homeostasis culminating in alterations in microbial communities (dysbiosis) and increased microbial translocation. Major questions remain on how interactions between translocating microbes and gut immune cells impact HIV-1-associated gut pathogenesis. We previously reported that in vitro exposure of human gut cells to enteric commensal bacteria upregulated the serine protease and cytotoxic marker Granzyme B (GZB) in CD4 T cells, and GZB expression was further increased in HIV-1-infected CD4 T cells. To determine if these in vitro findings extend in vivo , we evaluated the frequencies of GZB + CD4 T cells in colon biopsies and peripheral blood of untreated, chronically infected people with HIV-1 (PWH). Colon and blood GZB + CD4 T cells were found at significantly higher frequencies in PWH. Colon, but not blood, GZB + CD4 T cell frequencies were associated with gut and systemic T cell activation and Prevotella species abundance. In vitro , commensal bacteria upregulated GZB more readily in gut versus blood or tonsil-derived CD4 T cells, particularly in inflammatory T helper 17 cells. Bacteria-induced GZB expression in gut CD4 T cells required the presence of accessory cells, the IL-2 pathway and in part, MHC Class II. Overall, we demonstrate that GZB + CD4 T cells are prevalent in the colon during chronic HIV-1 infection and may emerge following interactions with translocated bacteria in an IL-2 and MHC Class II-dependent manner. Associations between GZB + CD4 T cells, dysbiosis and T cell activation suggest that GZB + CD4 T cells may contribute to gut HIV-1 pathogenesis.
T cell-based immunotherapies including genetically engineered T cells, adoptive transfer of tumor-infiltrating lymphocytes, and immune checkpoint blockade highlight the impressive anti-tumor effects of T cells. These successes have provided new hope to many cancer patients with otherwise poor prognoses. However, only a fraction of patients demonstrates durable responses to these forms of therapies and many develop significant immune-mediated toxicity. These heterogeneous clinical responses suggest that underlying nuances in T cell genetics, phenotypes, and activation states likely modulate the therapeutic impact of these approaches. To better characterize known genetic variations that may impact T cell function, we 1) review the function of early T cell receptor-specific signaling mediators, 2) offer a synopsis of known mutations and genetic alterations within the associated molecules, 3) discuss the link between these mutations and human disease and 4) review therapeutic strategies under development or in clinical testing that target each of these molecules for enhancing anti-tumor T cell activity. Finally, we discuss novel engineering approaches that could be designed based on our understanding of the function of these molecules in health and disease.
T Cell Lymphomas are a rare subtype of Lymphoma, occurring in ~1% of all cancers and response rates to current therapies reach only ~23%. The lack of unique targetable T cell antigens as well as their tendency to overcome chemotherapies results in a high incidence of relapse in most patients leading to remission rates of approximately two years. Immunotherapies, especially immune-checkpoint blockade, have slightly improved outcomes in refractory disease, but there remains a need for stronger and more durable responses. The chemotherapeutic potential of epigenetic modifiers is just beginning to be explored. HDAC inhibitors, DNA demethylating agents, and histone methyltransferase inhibitors reshape the transcriptome, potentially altering the expression of immune modulatory pathways. We hypothesized that pretreating T cell malignancies with epigenetic modifiers will alter key genetic signatures that sensitize them to CD8+ T cell-mediated cytotoxicity. We pretreated five T cell lymphoma cell lines, representative of different T cell malignant diseases with compounds from an FDA-approved 700+ epigenetic modifying drug library at four different concentrations and then co-cultured them with a tumor-reactive HLA-A2-matched primary (derived from PBMCs) cytotoxic CD8+ T cell line. Changes in T cell mediated cytotoxicity and alterations in immune modulating surface markers and potential CAR-T cell targets (CD30, CCR4, and CD47) were assessed by flow cytometry. Several promising compounds were identified by their ability to improve T cell mediated cytotoxicity, increase expression of immune stimulatory markers, decrease expression of immune inhibitory markers, and augment expression of existing CAR-T target antigens. Supported by NIH and the Colorado Clinical and Translational Sciences Institute (CCTSI)
<p>Supplementary Data Fig 2</p>
<p>Supplementary Data Fig 1</p>
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.