Sap is necessary for mediating antigen-specific effector functions of CD4+ AND CD8+ T cells

Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6−/− cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 TRM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway TRM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of TRM cells to different compartments of the lung and maintains airway TRM cells.

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Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8+T cells

Science Immunology ◽

10.1126/sciimmunol.aap9520 ◽

2019 ◽

Vol 4 (31) ◽

pp. eaap9520 ◽

Cited By ~ 21

Author(s):

Lelisa F. Gemta ◽

Peter J. Siska ◽

Marin E. Nelson ◽

Xia Gao ◽

Xiaojing Liu ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Tumor Infiltrating Lymphocytes ◽

Biochemical Basis ◽

Effector Functions ◽

Glycolytic Activity ◽

Functional Exhaustion ◽

Critical Insight ◽

Infiltrating Lymphocytes ◽

Insight Into

In the context of solid tumors, there is a positive correlation between the accumulation of cytotoxic CD8+tumor-infiltrating lymphocytes (TILs) and favorable clinical outcomes. However, CD8+TILs often exhibit a state of functional exhaustion, limiting their activity, and the underlying molecular basis of this dysfunction is not fully understood. Here, we show that TILs found in human and murine CD8+melanomas are metabolically compromised with deficits in both glycolytic and oxidative metabolism. Although several studies have shown that tumors can outcompete T cells for glucose, thus limiting T cell metabolic activity, we report that a down-regulation in the activity of ENOLASE 1, a critical enzyme in the glycolytic pathway, represses glycolytic activity in CD8+TILs. Provision of pyruvate, a downstream product of ENOLASE 1, bypasses this inactivity and promotes both glycolysis and oxidative phosphorylation, resulting in improved effector function of CD8+TILs. We found high expression of both enolase 1 mRNA and protein in CD8+TILs, indicating that the enzymatic activity of ENOLASE 1 is regulated posttranslationally. These studies provide a critical insight into the biochemical basis of CD8+TIL dysfunction.

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Epithelial adhesion molecules can inhibit HIV-1–specific CD8+ T-cell functions

Blood ◽

10.1182/blood-2010-12-321588 ◽

2011 ◽

Vol 117 (19) ◽

pp. 5112-5122 ◽

Cited By ~ 15

Author(s):

Hendrik Streeck ◽

Douglas S. Kwon ◽

Augustine Pyo ◽

Michael Flanders ◽

Mathieu F. Chevalier ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Antigenic Stimulation ◽

Effector Functions ◽

Cell Functions ◽

Natural Ligand ◽

Inhibitory Molecules ◽

Hiv 1 ◽

E Cadherin

Abstract Under persistent antigenic stimulation, virus-specific CD8+ T cells become increasingly dysfunctional and up-regulate several inhibitory molecules such as killer lectin-like receptor G1 (KLRG1). Here, we demonstrate that HIV-1 antigen-specific T cells from subjects with chronic-progressive HIV-1 infection have significantly elevated KLRG1 expression (P < .001); show abnormal distribution of E-cadherin, the natural ligand of KLRG1, in the intestinal mucosa; and have elevated levels of systemic soluble E-cadherin (sE-cadherin) that significantly correlate with HIV-1 viral load (R = 0.7, P = .004). We furthermore demonstrate that in the presence of sE-cadherin, KLRG1hi HIV-1–specific CD8+ T cells are impaired in their ability to respond by cytokine secretion on antigenic stimulation (P = .002) and to inhibit viral replication (P = .03) in vitro. Thus, these data suggest a critical mechanism by which the disruption of the intestinal epithelium associated with HIV-1 leads to increased systemic levels of sE-cadherin, which inhibits the effector functions of KLRG1hi-expressing HIV-1–specific CD8+ T cells systemically.

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Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions

Open Biology ◽

10.1098/rsob.160293 ◽

2016 ◽

Vol 6 (11) ◽

pp. 160293 ◽

Cited By ~ 5

Author(s):

Lee Kim Swee ◽

Zhen Wei Tan ◽

Anna Sanecka ◽

Nagisa Yoshida ◽

Harshil Patel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Toxoplasma Gondii ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Effector Function ◽

Effector Functions ◽

Physiological Conditions ◽

Cell Clones

T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity—hence reactivity to self—and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2 b haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 L d -restricted epitope, derived from the Rop7 protein of Toxoplasma gondii . We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon Toxoplasma gondii infection as well as effector function and TCR signalling upon antigenic stimulation in vitro . Antigen-independent TCR cross-linking in vitro uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds.

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Estimating the Precursor Frequency of Naive Antigen-specific CD8 T Cells

Journal of Experimental Medicine ◽

10.1084/jem.20001021 ◽

2002 ◽

Vol 195 (5) ◽

pp. 657-664 ◽

Cited By ~ 440

Author(s):

Joseph N. Blattman ◽

Rustom Antia ◽

David J.D. Sourdive ◽

Xiaochi Wang ◽

Susan M. Kaech ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Limit Of Detection ◽

Specific Antigen ◽

Fold Increase ◽

Cell Receptor ◽

Dependent Manner ◽

Specific Effector ◽

Precursor Frequency ◽

Lcmv Infection

The constraint of fitting a diverse repertoire of antigen specificities in a limited total population of lymphocytes results in the frequency of naive cells specific for any given antigen (defined as the precursor frequency) being below the limit of detection by direct measurement. We have estimated this precursor frequency by titrating a known quantity of antigen-specific cells into naive recipients. Adoptive transfer of naive antigen-specific T cell receptor transgenic cells into syngeneic nontransgenic recipients, followed by stimulation with specific antigen, results in activation and expansion of both donor and endogenous antigen-specific cells in a dose-dependent manner. The precursor frequency is equal to the number of transferred cells when the transgenic and endogenous responses are of equal magnitude. Using this method we have estimated the precursor frequency of naive CD8 T cells specific for the H-2Db–restricted GP33–41 epitope of LCMV to be 1 in 2 × 105. Thus, in an uninfected mouse containing ∼2-4 × 107 naive CD8 T cells we estimate there to be 100–200 epitope-specific cells. After LCMV infection these 100–200 GP33-specific naive CD8 T cells divide >14 times in 1 wk to reach a total of ∼107 cells. Approximately 5% of these activated GP33-specific effector CD8 T cells survive to generate a memory pool consisting of ∼5 × 105 cells. Thus, an acute LCMV infection results in a >1,000-fold increase in precursor frequency of DbGP33-specific CD8 T cells from 2 × 102 naive cells in uninfected mice to 5 × 105 memory cells in immunized mice.

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Quantitative Restoration of Immune Defense in Old Animals Determined by Naive Antigen-Specific CD8 T cell Numbers

10.1101/2021.08.09.453882 ◽

2021 ◽

Author(s):

Jennifer Uhrlaub ◽

Mladen Jergović ◽

Christine M. Bradshaw ◽

Sandip Sonar ◽

Christoper P. Coplen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Neutralizing Antibody ◽

Immune Defense ◽

Cell Numbers ◽

Specific Effector ◽

The Face ◽

Old Mice

Many older humans and animals exhibit reduced immune responses to infection and vaccination, and this often directly correlates to the numbers and frequency of naive T (Tn) cells. We found such a correlation between reduced numbers of blood CD8+ Tn cells and severe clinical outcomes of WNV in both humans naturally exposed to, and mice experimentally infected with, West Nile virus (WNV). To examine possible causality, we sought to increase the number of CD8 Tn cells by treating C57BL/6 mice with IL-7 complexes (IL-7C, anti-IL-7 mAb bound to IL-7), shown previously to efficiently increase peripheral T cell numbers by homeostatic proliferation. T cells underwent robust expansion following IL-7C administration to old mice increasing the number of total T cells (>four-fold) and NS4b:H-2Db-restricted antigen-specific CD8 T cells (two-fold). This improved the numbers of NS4b-specific CD8 T cells detected at the peak of the response against WNV, but not survival in the face of WNV challenge. IL-7C treated old animals also showed no improvement in WNV-specific effector immunity (neutralizing antibody and in vivo T cell cytotoxicity). To test quantitative limits to which CD8 Tn cell restoration could improve protective immunity, we transferred graded doses of Ag-specific precursors into old mice, and showed that injection of 5,400 (but not of 1,800 or 600) adult naive WNV-specific CD8 T cells significantly increased survival after WNV. These results set quantitative limits to the level of Tn reconstitution necessary to improve immune defense in older organisms, and are discussed in light of targets of immune reconstitution.

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Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination

10.1101/2020.09.03.281238 ◽

2020 ◽

Author(s):

Katja Müller ◽

Matthew P. Gibbins ◽

Arturo Reyes-Sandoval ◽

Adrian V. S. Hill ◽

Simon J. Draper ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Parasitophorous Vacuole ◽

Cd8 T Cell ◽

Major Protein ◽

Surface Coat ◽

Protective Antigens ◽

Malaria Vaccines ◽

Specific Effector

ABSTRACTVaccine discovery and development critically depends on predictive assays, which prioritise protective antigens. Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation, including phase I/II trials. Here, we tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8+ T cells either as an antigen in the circumsporozoite protein (CSP), the surface coat protein of extracellular sporozoites or in the upregulated in sporozoites 4 (UIS4), a major protein associated with the parasitophorous vacuole membrane (PVM) that surrounds the intracellular exo-erythrocytic forms (EEF). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust and superior antigen-specific CD8+ T cell responses, whilst an EEF antigen evokes poor responses. However, despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine-induced, antigen-specific effector CD8+ T cells results in high levels of protection when targeting both antigens. Our study is the first demonstration that poor immunogenicity of EEF antigens does not preclude their susceptibility to antigen-specific CD8+ T cell killing. Our findings that antigen immunogenicity is an inadequate predictor of vaccine susceptibility have wide-ranging implications on antigen prioritisation for the design and testing of next-generation pre-erythrocytic malaria vaccines.

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