N-acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner

ABSTRACT We recently found that an invasion of CD8+ cytotoxic T cells into tissue cysts of Toxoplasma gondii initiates an elimination of the cysts in association with an accumulation of microglia and macrophages. In the present study, we compared mRNA levels for 734 immune-related genes in the brains of infected SCID mice that received perforin-sufficient or -deficient CD8+ immune T cells at 3 weeks after infection. At 7 days after the T cell transfer, mRNA levels for only six genes were identified to be greater in the recipients of the perforin-sufficient T cells than in the recipients of the perforin-deficient T cells. These six molecules included two T cell costimulatory molecules, inducible T cell costimulator receptor (ICOS) and its ligand (ICOSL); two chemokine receptors, C-X-C motif chemokine receptor 3 (CXCR3) and CXCR6; and two molecules related to an activation of microglia and macrophages, interleukin 18 receptor 1 (IL-18R1) and chitinase-like 3 (Chil3). Consistently, a marked reduction of cyst numbers and upregulation of ICOS, CXCR3, CXCR6, IL-18R1, and Chil3 mRNA levels were also detected when the perforin-sufficient CD8+ immune T cells were transferred to infected SCID mice at 6 weeks after infection, indicating that the CD8+ T cell-mediated protective immunity is capable of eliminating mature T. gondii cysts. These results together suggest that ICOS-ICOSL interactions are crucial for activating CD8+ cytotoxic immune T cells to initiate the destruction of T. gondii cysts and that CXCR3, CXCR6, and IL-18R are involved in recruitment and activation of microglia and macrophages to the T cell-attacked cysts for their elimination. IMPORTANCE T. gondii establishes a chronic infection by forming tissue cysts, which can grow into sizes greater than 50 μm in diameter as a consequence of containing hundreds to thousands of organisms surrounded by the cyst wall within infected cells. Our recent studies using murine models uncovered that CD8+ cytotoxic T cells penetrate into the cysts in a perforin-dependent manner and induce their elimination, which is accompanied with an accumulation of phagocytic cells to the T cell-attacked target. This is the first evidence of the ability of the T cells to invade into a large target for its elimination. However, the mechanisms involved in anticyst immunity remain unclear. Immune profiling analyses of 734 immune-related genes in the present study provided a valuable foundation to initiate elucidating detailed molecular mechanisms of the novel effector function of the immune system operated by perforin-mediated invasion of CD8+ T cells into large targets for their elimination.

Download Full-text

MR1-Restricted T Cells in Cancer Immunotherapy

Cancers ◽

10.3390/cancers12082145 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2145

Author(s):

Pedro Flores-Villanueva ◽

Navid Sobhani ◽

Xu Wang ◽

Yong Li

Keyword(s):

T Cells ◽

Cytotoxic T Cells ◽

Acid Synthesis ◽

Cell Receptor ◽

Dependent Manner ◽

Mait Cells ◽

Mucosal Tissues ◽

Wide Range ◽

A Cell ◽

Cell Membrane Protein

Major histocompatibility complex class I-related (MR1) was first identified as a cell membrane protein involved in the development and expansion of a unique set of T cells expressing an invariant T-cell receptor (TCR) α-chain. These cells were initially discovered in mucosal tissues, such as the intestinal mucosa, so they are called mucosal-associated invariant T (MAIT) cells. MR1 senses the presence of intermediate metabolites of riboflavin and folic acid synthesis that have been chemically modified by the side-products of glycolysis, glyoxal or methylglyoxal. These modified metabolites form complexes with MR1 and translocate from the endoplasmic reticulum to the plasma membrane where MAIT cells’ TCRs recognize them. Recent publications report that atypical MR1-restricted cytotoxic T cells, differing from MAIT cells in TCR usage, antigen, and transcription factor profile, recognize an as yet unknown cancer-specific metabolite presented by MR1 in cancer cells. This metabolite may represent another class of neoantigens, beyond the neo-peptides arising from altered tumor proteins. In an MR1-dependent manner, these MR1-restricted T cells, while sparing noncancerous cells, kill many cancer cell lines and attenuate cell-line-derived and patient-derived xenograft tumors. As MR1 is monomorphic and expressed in a wide range of cancer tissues, these findings raise the possibility of universal pan-cancer immunotherapies that are dependent on cancer metabolites.

Download Full-text

The Lymphoid Chemokine CCL21 Enhances the Migration- and CTL-Inducing Functions of Dendritic Cells

Blood ◽

10.1182/blood.v118.21.1127.1127 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1127-1127

Author(s):

Cheol Yi Hong ◽

Pawel Kalinski ◽

Hyeoung-Joon Kim ◽

Je-Jung Lee

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Conflicts Of Interest ◽

Cytotoxic T Cells ◽

Lymphoid Organ ◽

Lymphoid Organs ◽

Dependent Manner ◽

Migratory Capacity ◽

Secondary Lymphoid Organs

Abstract Abstract 1127 The migration of dendritic cells (DCs) to secondary lymphoid organs is very important to elicit an adaptive immune response in cancer immunotherapy. Here, we show the effect of lymphoid cytokine on the ability of maturing DCs to migrate in response to the lymph node-associated chemokines. The secondary-lymphoid organ chemokine (SLC/CCL21) during DC maturation dramatically enhanced DC migratory capacity responding to CCL21 and CCL19, and, moreover, produced strongly enhanced cytotoxic T cells, although it did not affect the expression of cell surface markers such as CD80, CD83, CD86, and CCR7 and the production of cytokines such as IL-12p70, IL-10, and IL-23. Mature DCs (mDCs) exposed by chemokine produced higher levels of CXCL10 (IP-10) that is one of the chemokines involved in Th1 attraction, but did not affect the production of Th2-attracting cytokine CCL22, compared with unstimulated mDCs. CCL21-exposed DCs induced strongly enhanced numbers of the interferon-g (IFN-g)-expressing antigen-specific CD8+ T cells against tumor-specific antigens in an CXCL10-dependent manner. Cytotoxic CD8+ T cells stimulated with CCL21-exposed DCs expressed higher level of IFN-g than those stimulated with control mDCs. Interestingly, generation of cytotoxic T cells (CTLs) stimulated by TNFa/IL-1b/IL-6/PGE2-treated DCs (sDCs) supplemented with IP-10 produced strong cytotoxic T cells expressing higher level of IFN-g. Tetramer assay showed that CCL21-treated DCs enhanced generation of antigen-specific CTLs. Taken together, our data suggest that mDCs pre-stimulated by chemokine CCL21 enhanced migratory capacity to secondary lymphoid organs and produced strong cytotoxic T cells via IP-10 signaling pathway. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Rapid Expansion of Virus-Specific CD4+ T Cell Types in the CNS of Susceptible Mice Infected with Theiler’s Virus

International Journal of Molecular Sciences ◽

10.3390/ijms21207719 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7719

Author(s):

Hyun Seok Kang ◽

Wanqiu Hou ◽

Byung S. Kim

Keyword(s):

T Cells ◽

T Cell ◽

Viral Infection ◽

Cd4 T Cells ◽

Demyelinating Disease ◽

Cell Types ◽

Rapid Expansion ◽

Infection Model ◽

Dependent Manner ◽

Encephalomyelitis Virus

The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) induces a T cell-mediated demyelinating disease. This system has been studied as a relevant infection model for multiple sclerosis (MS). Therefore, defining the type of T cell responses and their functions is critically important for understanding the relevant pathogenic mechanisms. In this study, we adoptively transferred naive VP2-specific TCR-Tg CD4+ T cells into syngeneic susceptible SJL mice and monitored the development of the disease and the activation and proliferation of CD4+ T cells during the early stages of viral infection. The preexisting VP2-specific naive CD4+ T cells promoted the pathogenesis of the disease in a dose-dependent manner. The transferred VP2-specific CD4+ T cells proliferated rapidly in the CNS starting at 2–3 dpi. High levels of FoxP3+CD4+ T cells were found in the CNS early in viral infection (3 dpi) and persisted throughout the infection. Activated VP2-specific FoxP3+CD4+ T cells inhibited the production of IFN-γ, but not IL-17, via the same VP2-specific CD4+ T cells without interfering in proliferation. Thus, the early presence of regulatory T cells in the CNS with viral infection may favor the induction of pathogenic Th17 cells over protective Th1 cells in susceptible mice, thereby establishing the pathogenesis of virus-induced demyelinating disease.

Download Full-text

Abstract # 1773 Cytotoxic T cells may induce pain hypersensitivity in female but not male mice after nerve injury in an interferon-g-receptor-dependent manner

Brain Behavior and Immunity ◽

10.1016/j.bbi.2016.07.066 ◽

2016 ◽

Vol 57 ◽

pp. e19

Author(s):

B. Ham ◽

S. Rosen ◽

J. Austin ◽

J.S. Mogil

Keyword(s):

T Cells ◽

Nerve Injury ◽

Cytotoxic T Cells ◽

Dependent Manner ◽

Male Mice ◽

Pain Hypersensitivity

Download Full-text

Abstract 4798: Cytotoxic T cells kill tumor cells in a contact and antigen-dependent manner, but the interaction affects neighboring, non-target cells via interferon gamma secretion

10.1158/1538-7445.am10-4798 ◽

2010 ◽

Author(s):

Nicholas SR Sanderson ◽

Mariana Puntel ◽

Greg Baker ◽

Maria G. Castro ◽

Pedro R. Lowenstein

Keyword(s):

T Cells ◽

Tumor Cells ◽

Interferon Gamma ◽

Cytotoxic T Cells ◽

Target Cells ◽

Dependent Manner

Download Full-text

Lactate potentiates differentiation and expansion of cytotoxic T cells

10.1101/571745 ◽

2019 ◽

Cited By ~ 1

Author(s):

Helene Rundqvist ◽

Pedro Veliça ◽

Laura Barbieri ◽

Paulo A. Gameiro ◽

Pedro P. Cunha ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Progression ◽

T Cell Activation ◽

Cd8 T Cells ◽

Tumour Growth ◽

Tumour Progression ◽

Cytotoxic T Cells ◽

Malignant Tumour ◽

Dependent Manner

AbstractExercise has a range of effects on metabolism. In animal models, repeated exertion reduces malignant tumour progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effect of exercise on tumour progression is unclear, as are the cellular actors involved. We show here that exercise-induced reduction in tumour growth is dependent on CD8+ T cells and that lactate, which is produced at high levels during exertion, increases proliferative capacity and cytotoxicity of CD8+ T cells. We found that at elevated levels lactate is used as a fuel during T cell activation. We further found that injection of lactate into animals can reduce malignant tumour growth in a dose-and CD8+ T cell-dependent manner. These data demonstrate that lactate can act to increase the anti-tumour activity of cytotoxic T cells, and in so doing, reduce cancer progression.

Download Full-text

Insights on the mechanisms of the protective immunity in the brain from the studies on infection with an intracellular microorganism, Toxoplasma gondii

Medical Research Archives ◽

10.18103/mra.v9i11.2597 ◽

2021 ◽

Vol 9 (11) ◽

Author(s):

Yasuhiro Suzuki

Keyword(s):

T Cells ◽

Toxoplasma Gondii ◽

Cd8 T Cells ◽

Protective Immunity ◽

Early Stage ◽

Cytotoxic T Cells ◽

Host Cells ◽

Protective Mechanism ◽

Dependent Manner ◽

The Brain

The immune system operates the protection against infections by selecting efficient pathways depending on the pathogen. Toxoplasma gondii, an obligate intracellular protozoan parasite, has two lifecycle stages, tachyzoite and cyst, in intermediate hosts including humans. Tachyzoite is the acute stage form that quickly proliferates within host cells. Cyst is the chronic stage form that can slowly grow into more than 100 mm in diameter by containing hundreds to thousands of bradyzoites. Our studies on the IFN-g-mediated protective immunity against cerebral tachyzoite growth revealed that IFN-g production by brain-resident cells is not only required for upregulation of the innate protective immunity to limit cerebral tachyzoite proliferation during the early stage of the tachyzoite growth but also crucial for recruiting immune T cells from the periphery and activation of the recruited T cells to ultimately prevent the tachyzoite growth. Since IFN-g is crucial for the protective immunity against various intracellular microorganisms in the brain, it is possible that IFN-gproduced by brain-resident cells plays a key first line defense role by orchestrating both the innate and T cell-mediated protective immunity to control not only T. gondii but also the other intracellular pathogens. Our studies on the protective immunity against T. gondii cysts uncovered the capability of cytotoxic T cells to penetrate into the target in a perforin-dependent manner for its elimination. After penetrating into the target, the cytotoxic T cells secrete granzyme B, which associates with an accumulation of phagocytes to eliminate the parasite. Since the presence of tumor-infiltrating CD8+ T cells in solid cancers is an indicator of positive prognosis of cancer patients, the perforin-mediated penetration of CD8+ T cells and an accumulation of phagocytes could function as a powerful protective mechanism against not only T. gondiicysts but also targets of large mass in general such as solid cancers.

Download Full-text