Cognate Memory CD4+ T Cells Generated with Dendritic Cell Priming Influence the Expansion, Trafficking, and Differentiation of Secondary CD8+ T Cells and Enhance Tumor Control

Abstract 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.

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452 Combination treatment using KISIMATM protein-based cancer vaccine and systemic STING agonist results in profound modulation of tumor microenvironment and improved tumor control

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0452 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A479-A479

Author(s):

Matteo Rossi ◽

Elodie Belnoue ◽

Susanna Carboni ◽

Wilma Besson-Di Berardino ◽

Erika Riva ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Tumor Microenvironment ◽

Combination Therapy ◽

Cancer Vaccine ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Tumor Control ◽

Therapeutic Vaccination ◽

Potent Tumor

BackgroundKISIMATM platform allows the development of protein-based cancer vaccines able to induce a potent, tumor-specific CD8 and CD4 T cells response. While the cell penetrating peptide and the Anaxa portions confer, respectively, the cell delivery and self-adjuvanticity properties, the multiantigenic domain allows the targeting of different cancer antigens, resulting in anti-tumoral efficacy in different murine models.1 The first clinical candidate developed from KISIMATM is currently tested, together with anti-PD-1 blockade, in a phase I study in metastatic colorectal cancer patients. Stimulator of interferon genes agonists (STINGa) were shown to induce a potent type I interferon response in preclinical studies. The intratumoral administration of STINGa, to promote tumor inflammation, was shown to result in a protective spontaneous immune response in several murine tumor models. However, the encouraging preclinical results are not supported by recent clinical data, challenging the efficacy of unspecific monotherapy.As it is more and more clear that an effective cancer immunotherapy will require the combination of different treatment strategies, we investigate here the efficacy of combining KISIMATM cancer vaccine with STINGa treatment.MethodsMice were vaccinated with subcutaneous (s.c.) injection of KISIMATM vaccine combined with s.c. administration of STINGa. Safety and immunogenicity were assessed by measuring temperature, serum cytokines and the peripheral antigen-specific response. Anti-tumoral efficacy as well as in depth monitoring of TILs and tumor microenvironment modulation were assessed following therapeutic vaccination in a HPV16 E6 and E7 expressing TC-1 cold tumor model.ResultsCombination treatment was well tolerated and promoted the development of circulating antigen-specific CD8 T cells. In TC-1 tumor bearing mice, KISIMATM therapeutic vaccination resulted in the infiltration of both antigen-specific CD8 and CD4 T cells within the tumor, as well as a switch of tumor associated macrophages polarization toward the more inflammatory type 1. Combination therapy further increased the tumor microenvironment modulation induced by KISIMATM vaccine, promoting the polarization of inflammatory Thelper 1 CD4 T cells and increasing the effector function of antigen-specific CD8 T cells. The profound modulation of the tumor microenvironment induced by combination therapy enhanced the beneficial effect of KISIMATM vaccination, resulting in a prolonged tumor control.ConclusionsCombination of KISIMATM cancer vaccine with systemic STINGa treatment induces the development of a potent, tumor-specific immune response resulting in a profound modulation of the TME. As check-point inhibitor (CPI) therapy is ineffective on poorly infiltrated tumors, combination with therapies able to highly enhance tumor infiltration by T cells could expand CPI indications.Ethics ApprovalThe study was approved by the Canton of Geneva Ethic Board, under the license number GE165/19ReferenceBelnoue E, et al. Targeting self and neo-epitopes with a modular self-adjuvanting cancer vaccine. JCI Insight 2019. 4:11.

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Dendritic Cell–MHC Class II and Itk Regulate Functional Development of Regulatory Innate Memory CD4+ T Cells in Bone Marrow Transplantation

The Journal of Immunology ◽

10.4049/jimmunol.1303176 ◽

2014 ◽

Vol 192 (7) ◽

pp. 3435-3441 ◽

Cited By ~ 6

Author(s):

Weishan Huang ◽

Qian Qi ◽

Jianfang Hu ◽

Fei Huang ◽

Terri M. Laufer ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

Dendritic Cell ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Marrow Transplantation ◽

Class Ii ◽

Functional Development ◽

Memory Cd4 T Cells

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Faculty Opinions recommendation of Dendritic cell-MHC class II and Itk regulate functional development of regulatory innate memory CD4+ T cells in bone marrow transplantation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718304946.793492604 ◽

2014 ◽

Author(s):

Edward Collins ◽

Brandon Linz

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

Dendritic Cell ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Marrow Transplantation ◽

Class Ii ◽

Functional Development ◽

Memory Cd4 T Cells

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343. T-cell Subsets Associated with Diabetes in Veterans with and without HIV

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.416 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S182-S183

Author(s):

Samuel Bailin ◽

Kathleen McGinnis ◽

Wyatt J McDonnell ◽

Kaku So-Armah ◽

Melissa Wellons ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Immune Activation ◽

Cd4 T Cells ◽

T Cell Subsets ◽

Effector Memory ◽

Hiv Status ◽

Adaptive Immune ◽

Memory Cd4 T Cells

Abstract Background Depletion of naïve CD4+ T cells and elevated adaptive immune activation are hallmarks of HIV infection. Higher proportions of memory CD4+ T cells are associated with prevalent diabetes in the general population, but few studies of persons with HIV (PWH) exist. Methods We analyzed data from 1532 PWH and 836 uninfected veterans in the longitudinal Veterans Aging Cohort Study (VACS), which archived peripheral mononuclear cells from these veterans between 2005 and 2007. We used flow cytometry to phenotype CD4+ and CD8+ T cells, including naïve, activated CD38+, senescent CD57+, total memory, and memory subsets. Prevalent diabetes (at blood collection) was identified in the VA electronic medical record using random glucose, hemoglobin A1c, ICD-9 codes, and medication. Cases were validated by two-physician chart review. We used multivariate logistic regression models adjusted for age, gender, body mass index, race/ethnicity, unhealthy alcohol use, hepatitis C, CMV status, and viral suppression stratified by HIV status to identify T-cell subsets associated with diabetes in PWH and uninfected. Results The cohort was 95% male, 68% African-American, and 22% diabetic. Higher CD4+CD45RO+ memory T cells were associated with prevalent diabetes in the uninfected and in PWH (P = 0.03 and P = 0.07, respectively; Figure A). Among subsets, diabetes was associated with higher transitional memory CD4+ T cells in the uninfected (P = 0.01), but higher central memory cells (P = 0.02) and lower effector memory cells (P = 0.04) in PWH. T effector memory RA+ cells were not associated with diabetes. Lower senescent CD4+CD57+ T cells were associated with diabetes in both PWH and uninfected (P = 0.03 and P = 0.04, respectively; Figure B), but results for naïve CD8+ T cells diverged: diabetes was associated with higher naïve CD8+cells in PWH but lower in uninfected (P = 0.01 and P < 0.01, respectively; Figure C). We assessed interaction by HIV status in a pooled model, which was only significant for the naïve CD8+ T cells (P = 0.01). Conclusion The adaptive immune profile associated with prevalent diabetes was similar by HIV status and characterized by a shift in CD4+ T cells from senescent to memory phenotypes, suggesting that chronic immune activation contributes to the higher risk of diabetes in PWH. Disclosures All authors: No reported disclosures.

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Granzyme B secretion by human memory CD4 T cells is less strictly regulated compared to memory CD8 T cells

BMC Immunology ◽

10.1186/s12865-014-0036-1 ◽

2014 ◽

Vol 15 (1) ◽

Cited By ~ 23

Author(s):

Lin Lin ◽

Jacob Couturier ◽

Xiaoying Yu ◽

Miguel A Medina ◽

Claudia A Kozinetz ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Granzyme B ◽

Human Memory ◽

Memory Cd8 T Cells ◽

Memory Cd4 T Cells

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CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response

PLoS ONE ◽

10.1371/journal.pone.0180644 ◽

2017 ◽

Vol 12 (7) ◽

pp. e0180644 ◽

Cited By ~ 8

Author(s):

Aleksandr Barinov ◽

Alessia Galgano ◽

Gerald Krenn ◽

Corinne Tanchot ◽

Florence Vasseur ◽

...

Keyword(s):

T Cells ◽

Dendritic Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Complexes

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The activation of memory CD4+ T cells and CD8+ T cells in patients with multiple sclerosis

Yearbook of Neurology and Neurosurgery ◽

10.1016/s0513-5117(08)70055-3 ◽

2007 ◽

Vol 2007 ◽

pp. 81-82

Author(s):

S. Delgado

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Memory Cd4 T Cells

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CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses

Journal of Experimental Medicine ◽

10.1084/jem.20181365 ◽

2019 ◽

Vol 216 (5) ◽

pp. 1214-1229 ◽

Cited By ~ 46

Author(s):

Lalit K. Beura ◽

Nancy J. Fares-Frederickson ◽

Elizabeth M. Steinert ◽

Milcah C. Scott ◽

Emily A. Thompson ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Activation ◽

Immune Cell ◽

Memory T Cells ◽

Cell Immunity ◽

And Migration ◽

Resident Memory T Cells ◽

Memory Cd4 T Cells

This study examines the extent to which memory CD4+ T cells share immunosurveillance strategies with CD8+ resident memory T cells (TRM). After acute viral infection, memory CD4+ T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8+ T cells. In contrast, memory CD4+ T cells were more likely to be resident within lymphoid organs than CD8+ T cells. Migration properties of memory-phenotype CD4+ T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4+ and CD8+ TRM shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property–specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4+ TRM reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4+ T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8+ T cells.

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