scholarly journals CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+ CD8+ T cells in mice

2020 ◽  
Author(s):  
Takayoshi Yamauchi ◽  
Toshifumi Hoki ◽  
Takaaki Oba ◽  
Kristopher Attwood ◽  
Xuefang Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Cell Subset ◽  
Antitumor Efficacy ◽  
Preclinical Model ◽  
Therapeutic Vaccines ◽  
T Cell Subset

AbstractThe use of tumor mutation-derived neoantigen represents a promising approach for cancer vaccines. Preclinical and early-phase human clinical studies have shown the successful induction of tumor neoepitope-directed responses; however, overall clinical efficacy of neoantigen vaccines has been limited. One major obstacle of this strategy is the prevailing lack of sufficient understanding of the mechanism underlying the generation of neoantigen-specific CD8+ T cells. Here, we report a correlation between antitumor efficacy of neoantigen/toll-like receptor 3 (TLR3)/CD40 vaccination and the generation of antigen-specific CD8+ T cells expressing CX3C chemokine receptor 1 (CX3CR1) in a preclinical model. Mechanistic studies using mixed bone marrow chimeras identified that CD40 and CD80/86, but not CD70 signaling in Batf3-dependent conventional type 1 dendritic cells (cDC1s) is required for antitumor efficacy of neoantigen vaccine and generation of neoantigen-specific CX3CR1+ CD8+ T cells. Although CX3CR1+ CD8+ T cells exhibited robust in vitro effector function, depletion of this subset did not alter the antitumor efficacy of neoantigen/TLR3/CD40 agonists vaccination, suggesting that the expanded CX3CR1+ CD8+ T cell subset represents the post-differentiated in vivo effective CX3CR1-negative CD8+ T cell subset. Taken together, our results reveal a critical role of CD40 and CD80/86 signaling in cDC1s in antitumor efficacy of neoantigen-based therapeutic vaccines, and implicate the potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine therapy.

scholarly journals Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice

2021 ◽  
Vol 118 (23) ◽  
pp. e2103730118
Author(s):  
Yuka Nakajima ◽  
Kenji Chamoto ◽  
Takuma Oura ◽  
Tasuku Honjo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Critical Role ◽  
Cell Subset ◽  
Effector Memory ◽  
T Cell Subset ◽  
Aged Mice ◽  
Age Related

CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism–related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1–deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

scholarly journals Cytotoxic Activity and Memory T Cell Subset Distribution of in vitro-Stimulated CD8+ T Cells Specific for HER2/neu Epitopes

2019 ◽  
Vol 10 ◽  
Author(s):  
Maria Kuznetsova ◽  
Julia Lopatnikova ◽  
Julia Shevchenko ◽  
Alexander Silkov ◽  
Amir Maksyutov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic Activity ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
T Cell Subset ◽  
Memory T Cell ◽  
Subset Distribution

scholarly journals Phenotypic and Functional Separation of Memory and Effector Human CD8+ T Cells

1997 ◽  
Vol 186 (9) ◽  
pp. 1407-1418 ◽  
Author(s):  
Dörte Hamann ◽  
Paul A. Baars ◽  
Martin H.G. Rep ◽  
Berend Hooibrink ◽  
Susana R. Kerkhof-Garde ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Fas Ligand ◽  
Cytotoxic T Lymphocyte ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Cytolytic Activity ◽  
T Cell Subset

Human CD8+ memory- and effector-type T cells are poorly defined. We show here that, next to a naive compartment, two discrete primed subpopulations can be found within the circulating human CD8+ T cell subset. First, CD45RA−CD45R0+ cells are reminiscent of memory-type T cells in that they express elevated levels of CD95 (Fas) and the integrin family members CD11a, CD18, CD29, CD49d, and CD49e, compared to naive CD8+ T cells, and are able to secrete not only interleukin (IL) 2 but also interferon γ, tumor necrosis factor α, and IL-4. This subset does not exert cytolytic activity without prior in vitro stimulation but does contain virus-specific cytotoxic T lymphocyte (CTL) precursors. A second primed population is characterized by CD45RA expression with concomitant absence of expression of the costimulatory molecules CD27 and CD28. The CD8+CD45RA+CD27− population contains T cells expressing high levels of CD11a, CD11b, CD18, and CD49d, whereas CD62L (L-selectin) is not expressed. These T cells do not secrete IL-2 or -4 but can produce IFN-γ and TNF-α. In accordance with this finding, cells contained within this subpopulation depend for proliferation on exogenous growth factors such as IL-2 and -15. Interestingly, CD8+CD45RA+CD27− cells parallel effector CTLs, as they abundantly express Fas-ligand mRNA, contain perforin and granzyme B, and have high cytolytic activity without in vitro prestimulation. Based on both phenotypic and functional properties, we conclude that memory- and effector-type T cells can be separated as distinct entities within the human CD8+ T cell subset.

scholarly journals Elimination of syngeneic sarcomas in rats by a subset of T lymphocytes.

1980 ◽  
Vol 152 (4) ◽  
pp. 823-841 ◽  
Author(s):  
E Fernandez-Cruz ◽  
B A Woda ◽  
J D Feldman
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Subset ◽  
Suppressor Cells ◽  
Effector Cells ◽  
Long Duration ◽  
Ia Antigens

Established subcutaneous Moloney sarcomas (MST-1) of large size and long duration were eliminated from syngeneic rats by intravenous infusion of varying numbers of specific syngeneic effector T lymphocytes. Spleen cells from BN rats in which tumor had regressed were cultured in an in vitro mixed lymphocyte tumor cell culture (MLTC) to augment cytotoxicity of effector cells. In the MLTC a T cell subset was expanded in response to MST-1 antigens and transformed into blast elements. With these changes, there was an increase in the W3/25 antigen on the T cell surface, a decrease of W3/13 antigen, and an increase in the number of T cells with Ia antigens. The subset associated with elimination of established tumors was a blast T cell W3/25+, W3/13+, as detected by monoclonal antibodies to rat T antigens. The W3/25+ subset was poorly cytotoxic in vitro for MST-1 and apparently functioned in vivo as an amplifier or helper cell in the tumor-bearing host. The W3/25- population was a melange of cells that included (W3/13+, W3/25-) T cells, null cells, Ig+ cells, and macrophages, and was associated with enhancement of tumor in vivo, suggesting the presence of suppressor cells.

Apoptotic Pathways of Human Regulatory T Cells in Chronic Graft Versus Host Disease (cGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 225-225
Author(s):  
Kazuyuki Murase ◽  
Yutaka Kawano ◽  
Jeremy Ryan ◽  
Ken-ichi Matsuoka ◽  
Gregory Bascug ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Low Dose ◽  
Cell Subset ◽  
Mitochondrial Pathway ◽  
T Cell Subsets ◽  
T Cell Subset ◽  
Mitochondrial Membrane Depolarization

Abstract Abstract 225 CD4+CD25+Foxp3+ regulatory T cells (Treg) are known to play a central role in the maintenance of self-tolerance and immune homeostasis. After allogeneic stem cell transplantation, impaired recovery of Treg is associated with the development of cGVHD. Interleukin-2 (IL-2) is a critical regulator of Treg development, expansion and survival and lack of IL-2 results in Treg deficiency. In patients with cGVHD, we previously demonstrated that Treg proliferate at high levels but this subset is also highly susceptible to apoptosis leading to inadequate Treg numbers (Matsuoka et al. JCI 2010). We also reported that low-dose IL-2 administration resulted in selective expansion of Treg in vivo and clinical improvement of cGVHD (Koreth et al. NEJM 2011). To identify mechanisms responsible for increased Treg susceptibility to apoptosis in cGVHD we used a new flow cytometry-based assay to measure mitochondrial membrane depolarization in response to a panel of pro-apoptotic BH3 peptides (BIM, BID, BAD, NOXA, PUMA, BMF, HRK). This assessment allowed us to compare BH3 peptide-induced mitochondrial membrane depolarization (“priming”) in different T cell subsets, including CD4 Treg, conventional CD4 T cells (CD4 Tcon), and CD8 T cells. Expression of Bcl-2, CD95 and Ki67 were also studied in each T cell subset. We studied peripheral blood samples from 36 patients with hematologic malignancies (median age 59 yr) who are > 2 years post HSCT (27 patients with cGVHD and 9 patients without cGVHD) and 15 patients who received daily subcutaneous IL-2 for 8 weeks for treatment of steroid-refractory cGvHD. Severity of cGVHD was classified according to NIH criteria. In patients without cGVHD, BH3 priming was similar in all 3 T cell subsets (CD4 Treg, CD4 Tcon and CD8). In patients with cGVHD, CD4 Treg were more primed than CD4 Tcon when challenged with BIM, BAD, PUMA, BMF and the combination of BAD + NOXA peptides (p<0.01 – 0.0001). Treg were more primed than CD8 T cells when challenged with PUMA peptide (p<0.0001), but priming in Treg and CD8 T cells was similar for other BH3 peptides in patients with cGVHD. We also compared BH3 priming of each T cell subset in patients with different grades of cGVHD. When challenged with BH3 peptides, Treg, Tcon and CD8 T cells were less primed in patients with severe cGVHD. In patients with cGVHD, Treg expressed higher levels of Ki-67, higher levels of CD95 and lower levels of Bcl-2 than Tcon. Expression of CD95 did not vary with severity of GVHD in any T cell subset, but expression of Bcl-2 was significantly increased in all subsets in patients with severe cGVHD. Increased BH3 priming and high expression of CD95 indicate that Treg are more susceptible to apoptosis than Tcon in cGVHD. However, both Treg and Tcon become less primed and Bcl-2 levels increase in severe cGVHD suggesting that these cells are less susceptible to mitochondrial pathway apoptosis. Since the total number of Treg and Tcon are significantly reduced in patients with cGVHD, these findings suggest that the remaining circulating cells are relatively resistant to mitochondrial pathway apoptosis. CD95 expression in Treg remains high indicating no change in death receptor pathway apoptosis. Daily treatment with low-dose IL-2 for 8 weeks selectively expands Treg in vivo in patients with severe cGVHD. As the number of Treg increase, BH3 profiling shows that these cells gradually become more primed and therefore more susceptible to mitochondrial pathway apoptosis. Taken together, these studies help define the complex and distinct pathways that regulate survival in different T cell subsets and changes in these pathways that occur in patients with chronic GVHD. These pathways play important roles in the maintenance of T cell homeostasis and targeting these complex pathways can provide new opportunities to promote immune tolerance after allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Thalidomide Costimulates Primary Human T Lymphocytes, Preferentially Inducing Proliferation, Cytokine Production, and Cytotoxic Responses in the CD8+ Subset

1998 ◽  
Vol 187 (11) ◽  
pp. 1885-1892 ◽  
Author(s):  
Patrick A.J. Haslett ◽  
Laura G. Corral ◽  
Matthew Albert ◽  
Gilla Kaplan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
T Cell Subset ◽  
Human T Cell

The efficacy of thalidomide (α-phthalimido-glutarimide) therapy in leprosy patients with erythema nodosum leprosum is thought to be due to inhibition of tumor necrosis factor α. In other diseases reported to respond to thalidomide, the mechanism of action of the drug is unclear. We show that thalidomide is a potent costimulator of primary human T cells in vitro, synergizing with stimulation via the T cell receptor complex to increase interleukin 2–mediated T cell proliferation and interferon γ production. The costimulatory effect is greater on the CD8+ than the CD4+ T cell subset. The drug also increases the primary CD8+ cytotoxic T cell response induced by allogeneic dendritic cells in the absence of CD4+ T cells. Therefore, human T cell costimulation can be achieved pharmacologically with thalidomide, and preferentially in the CD8+ T cell subset.

scholarly journals The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions

2019 ◽  
Vol 5 (7) ◽  
pp. eaav9732 ◽  
Author(s):  
Carina Seitz ◽  
Juan Huang ◽  
Anna-Lena Geiselhöringer ◽  
Pamela Galbani-Bianchi ◽  
Svenja Michalek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nuclear Receptor ◽  
Transcriptional Control ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Orphan Nuclear Receptor ◽  
Cell Functions

LRH-1 (liver receptor homolog-1/NR5a2) is an orphan nuclear receptor, which regulates glucose and lipid metabolism, as well as intestinal inflammation via the transcriptional control of intestinal glucocorticoid synthesis. Predominantly expressed in epithelial cells, its expression and role in immune cells are presently enigmatic. LRH-1 was found to be induced in immature and mature T lymphocytes upon stimulation. T cell–specific deletion of LRH-1 causes a drastic loss of mature peripheral T cells. LRH-1–depleted CD4+ T cells exert strongly reduced activation-induced proliferation in vitro and in vivo and fail to mount immune responses against model antigens and to induce experimental intestinal inflammation. Similarly, LRH-1–deficient cytotoxic CD8+ T cells fail to control viral infections. This study describes a novel and critical role of LRH-1 in T cell maturation, functions, and immopathologies and proposes LRH-1 as an emerging pharmacological target in the treatment of T cell–mediated inflammatory diseases.

scholarly journals Engineered red blood cells as an off-the-shelf allogeneic anti-tumor therapeutic

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuqing Zhang ◽  
Mengyao Luo ◽  
Shamael R. Dastagir ◽  
Mellissa Nixon ◽  
Annie Khamhoung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Cellular Immunotherapy ◽  
Tumor Control

AbstractCheckpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E711-19, 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential ‘off-the-shelf’ in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.

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