bluuebunny/crossref_metadata_2025_split huggingface dataset:
A T cell-dependent mechanism for the induction of human mucosal homing IgA-secreting plasmablasts (39.5)
Authors: Dullaers Melissa , Li Dapeng , Xue Yaming , Ni Ling , Gayet Ingrid , Banchereau Jacques , Oh Sangkon 
Published: January 2023

Abstract
Mucosal IgA secreted by local plasma cells (PCs) is a critical component of mucosal immunity. Although IgA class switching can occur at mucosal sites in a T cell-independent manner, high-affinity PCs are optimally generated in germinal centers (GCs) in a T cell-dependent fashion. However, the mechanism of how CD4+ helper T cells induce mucosal-homing IgA-PCs remains unclear.
We show here that TGFb1 and IL-21, produced by follicular helper T cells (TFH), synergize to generate abundant IgA-plasmablasts (PBs) that express CCR10. In the presence of IL-21, TGFb1 promotes naive B cell proliferation and differentiation. In addition it overrides IL-21-induced IgG class switching in favor of IgA. Furthermore, in combination with IL-21, TGFb1 downregulates CXCR5, while upregulating CCR10 on PBs, enabling their exit from GCs and migration towards local mucosa. This is supported by the presence of CCR10+IgA+ cells in tonsil GCs.
In conclusion, TFH, through IL-21 and TGFb1 contribute to the generation of human mucosal-homing IgA+ PCs. Thus, mucosal vaccines should aim to induce robust TFH responses.
α-GalCer is an effective mucosal adjuvant for repeated nasal or oral delivery of HIV peptide antigens (39.54)
Authors: Courtney Amy N , Thapa Prakash , Nehete Pramod N , Li Chun , Zhou Dapeng , Sastry K. Jagannadha 
Published: January 2023

Abstract
Mucosal vaccine delivery is important for strong immune responses at biologically relevant sites, however weakly immunogenic antigens delivered by the mucosal route may induce tolerance. Therefore, appropriate adjuvants should be included for effective mucosal immunization. Mice were immunized by the oral or nasal route with alpha-Galactosylceramide (α-GalCer) as an adjuvant for co-administering with a CTL-inducing HIV envelope peptide (R15K). We observed antigen-specific cellular immune responses in multiple systemic and mucosal tissues. Contrary to the known potential of repeated parenteral dosing with α-GalCer to induce NKT cell anergy that could compromise adoptive immunity, we observed that multiple doses delivered by mucosal routes were more efficient in priming broader antigen-specific immune responses. We also obtained results showing that poly-lactic acid based nanoparticles conjugated with α-GalCer can repeatedly stimulate NKT cells both in vitro and in vivo without inducing anergy. Mechanistic studies showed that nanoparticle-formulated α-GalCer is efficiently presented by mouse CD11c+ dendritic cells and CD11b+ macrophages, but very poorly by B220+ B cells. These results demonstrate the effectiveness of α-GalCer as an adjuvant for repeated administration of vaccines for protection against mucosally transmitted pathogens.
Vitamin D is required for the development of functional CD8{alpha}{alpha} intestinal intraepithelial lymphocytes (39.7)
Authors: Bruce Danny W , Cantorna Margherita T 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) is an autoimmune disease that affects the gastrointestinal tract. Vitamin D an immunoregulatory steroid hormone has been shown to have suppressive affects on IBD and vitamin D deficiency has been shown to have a direct correlation with the severity of inflammation in experimental models of the disease. Several regulatory cells including CD8αα + TCRαβ + T cells that are found in the epithelial layer of the gut, have been shown to suppress experimental models of IBD. Here we show that mice that lack the vitamin D receptor (VDR) or are vitamin D deficient have significantly reduced CD8αα + TCRαβ + T cells. When vitamin D is provided to deficient mice this population of T cells recovers. Precursors of CD8αα + TCRαβ + T cells in the thymus of VDR deficient mice appear to be normal. However, gut homing of the CD8αα + TCRαβ + T cells precursors is reduced. Those CD8αα + TCRαβ + T cells that are in the gut of mice that lack the VDR produce fewer cytokines and appear to be dysfunctional. Vitamin D and signaling through the VDR is required for the development of functional CD8αα + TCRαβ + T cells.
CLEC2A Is a Novel Skin-Specific, Stimulatory Ligand of Human NK Cells (39.8)
Authors: Steinle Alexander , Stejfova Veronika , Kuttruff Sabrina , Schittek Birgit , Spreu Jessica 
Published: January 2023

Abstract
The Natural Killer Gene Complex (NKC) encodes for numerous C-type lectin-like receptors (CTLR) variably expressed on lymphocytes and myeloid cells. Well-known representatives of NKC-encoded CTLR are NKG2D, CD69, and Ly49 molecules. However, the NKC also contains a considerable number of genes which are barely characterized. Recently, we described the CLEC2A gene encoding for a new member of the human CLEC2 family of NKC-encoded CTLR. CLEC2A, in contrast to other human CLEC2 family members such as CD69/CLEC2C and AICL/CLEC2B, is virtually not expressed by peripheral leukocytes, but its expression appears restricted to skin. We now report that CLEC2A encodes for a non-disulfide-linked, homodimeric surface CTLR which is expressed on freshly isolated skin cells. Addressing a potential immune-associated function, we find that CLEC2A stimulates cytotoxicity and cytokine release of human NK cells. However, we failed to ascertain CLEC2A engagement by known activating NK receptors. Instead, we identified a hitherto undescribed NKC-encoded CTLR (NKp65) that specifically interacts with CLEC2A and activates NK cytotoxicity. In summary, we define CLEC2A as a skin-specific and NK cell-stimulating CTLR engaging NKp65, a novel activating CTLR which may allow for dedicated immunosurveillance of human skin.
This work was supported by funds (SFB 685/A1) of the German Research Foundation (DFG).
Identification of in vivo 6-thioguanine-resistant T cells reactive to melanoma-associated antigens (40.15)
Authors: Zuleger Cindy L , Macklin Michael D , Pei Qinglin , Newton Michael A , Albertini Mark R 
Published: January 2023

Abstract
T cells from melanoma patients (MEL) can mediate in vitro anti-tumor and regulatory functions. We hypothesize that in vivo hypoxanthine-guanine phosphoribosyltransferase-deficient T cells (MT) from MEL are enriched for T cells undergoing repetitive in vivo cell division in response to melanoma. MT were selected with 6-thioguanine (TG) from MEL PBMC as clonal isolates or as mass cultures, and from tumor-bearing tissues as mass cultures. Wild-type T cells (WT) were obtained analogously, without TG selection. TCR beta chain (TCRB) cDNA sequence analysis identified significantly enriched T cell clonal amplifications in MT compared to WT: 3 of 6 PBMC clonal isolate assays (p ≤ 0.05); 6 of 6 PBMC mass cultures (p &lt; 0.001); 5 of 5 tumor mass cultures (p &lt; 0.005). Identical TCRB sequences were found within and between MEL, in PBMC and tumor, demonstrating trafficking of T cell clones and suggesting shared immunogenic melanoma antigens. Using peptide-MHC pentamers, a significant enrichment of melanoma-specific T cells in MT compared to WT was demonstrated in 3 of 5 tumor mass cultures (p &lt; 0.001). Preliminary data from MT in a tumor suggest that some MT possess specific reactivity to melanoma peptide-pulsed targets in vitro. We conclude that MT from tumor sites are enriched for T cells responding in vivo to melanoma and provide candidate probes into the immunobiology of melanoma.
Supported by a VA Merit Grant and gifts to the UWCCC.
Using T Cell Responses In The Lymph Node To Predict Patient Outcome In Colorectal Cancer (40.16)
Authors: Kemp Roslyn A , Yoon Han-Seung , Anjomshoaa Ahmad , Reeve Anthony E 
Published: January 2023

Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide - over half of those diagnosed will die from the disease. An important role for the immune response in controlling CRC has been demonstrated in numerous animal models and in human patients. The extent of T cell infiltration in the primary tumour is a better predictor of survival in CRC patients than traditional staging. Further, recent data by our lab and others have shown a correlation between immune response gene expression and favourable patient outcome. Despite the presence of an immune response, tumours still develop and grow. We hypothesised that the T cell response in the lymph nodes, i.e. the site of immune response initiation, may be a better predictor of patient outcome than that of the primary tumour. To this end, we analysed T cell subsets in the lymph nodes of Dukes' Stage B colorectal cancer (non metastatic) in a cohort of patients from New Zealand who had clinical follow-up. We found that, as is true for CD8+ T cells infiltrating the primary tumour, the number of CD8+ T cells on the lymph nodes correlated with a favourable patient outcome. However, the number of total CD4+ T cells in the lymph node was not correlated with patient outcome. The subtypes of CD4+ and CD8+ T cells, e.g. regulatory, effector, memory, are yet to be investigated. However, our data shows that the anti-tumour immune response appears to be initiated effectively in the lymph node and implies that the tumour environment may act directly to down-modulate an effective immune response.
Assessment of telomerase inactivation in T cell responses and antitumor immunity (40.28)
Authors: Gong Jianlin , Koido Shigeo , Liu Chunlei 
Published: January 2023

Abstract
Telomerase knockout (mTerc-/-) mice expressing polyoma middle T oncogene (PyMT) in 4 generations were immunized with fusions of dendritic cells and MUC1-positive mammary tumor cells (FC/MMT). Both CD4 and CD8 T cells from immunized MMT mice divided vigorously as measured by CFSE labeling. Comparable cell division was observed in T cells from immunized G0 mTerc+/-MMT, G1 and G2 mTerc-/-MMT mice. In contrast, cell division decreased in T cells from G3 mTerc-/-MMT mice. CTL against mammary tumor cells were induced in LNC and Splenocytes from immunized but not non-immunized early generations of mTerc-/-MMT mice. However, CTL in the late generations of immunized mTerc-/-MMT mice decreased. Finally, the efficacy of immunotherapy in the prevention and treatment of spontanenous mammary carcinomas was assessed. In the prevention study, the time required for the mammary tumors in MMT, G0 mTerc+/-MMT, G1, G2 and G3 mTerc-/-MMT mice immunized with FC/MMT were 124.7±3.8, 118.6±10.8, 139.9±25.3, 138±12.1 and 146.8±21.2 days, respectively. The time required for the mammary tumor development in MMT, G0 mTerc+/-MMT, G1, G2 and G3 mTerc-/-MMT mice immunized with FC/MMT in the treatment study were 112.4±10.4, 113.6±8.4, 136.3±10, 144.3±12.7 and 158.7±15.7 days, respectively. In contrast, the latency time for tumor development in MMT, G0 mTerc+/-MMT, G1, G2 and G3 mTerc-/-MMT mice without immunization were 73.07±28.03, 96.07±28.79, 115.6±8.88, 117.14±32.1 and 127.11±35.84 days, respectively. The difference of time required for tumor development between mice with or without vaccination in both prevention and treatment studies is statistically significant.
Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T cell anergy in vivo (40.30)
Authors: Redmond William , Gough Michael , Weinberg Andrew 
Published: January 2023

Abstract
Tumor-specific CD8 T cell peripheral tolerance occurs through a variety of mechanisms including clonal deletion, suppression, and the induction of anergy and is an important barrier that limits the generation of anti-tumor immunity. Several groups have demonstrated that prostate cancer can render tumor-specific CD8 T cells anergic, suggesting that strategies to reverse tumor-induced anergy may augment anti-tumor immunity. Recent work has demonstrated that signaling through the OX40 (CD134) co-stimulatory receptor, a member of the TNFR super-family, can augment both CD4 and CD8 T cell expansion, differentiation, and the generation of memory cells. However, whether OX40 ligation can reverse CD8 T cell anergy, and more specifically, tumor-induced CD8 T cell anergy, remains unclear. In the current study, we demonstrate that OX40 ligation can reverse CD8 T cell anergy to a prostate-specific self-antigen in non-tumor bearing hosts. Furthermore, OX40 engagement reversed tumor-specific CD8 T cell anergy and restored the proliferative capacity of tumor-reactive CD8 T cells in vivo, which attenuated the extent of tumor growth and enhanced the survival of tumor-bearing hosts. This is the first demonstration that OX40 ligation can rescue the function of anergic self or tumor-reactive CD8 T cells in vivo and suggests that OX40-mediated therapy may provide a novel means of boosting anti-tumor immunity by restoring the responsiveness of previously anergic tumor-specific CD8 T cells.
Supported by an American Cancer Society - Sam E. and Kathleen Henry post-doctoral fellowship, a Prostate Cancer Foundation Young Investigator Award (W.L.R.), and grants from the NIH (A.D.W.).
NKT activation together with blockade of PD-L1 pathway lead to enhanced tumor responses (40.32)
Authors: Latchman Yvette E , Durgan Kevin , Warner Paul 
Published: January 2023

Abstract
Invariant NKT cells (iNKT cells) are a unique population of lymphocytes that have a biased TCR gene expression, are restriction by CD1d molecules, and rapidly produce a spectrum of cytokines following activation. Various studies have shown that positive costimulatory pathways can influence the activation of iNKT cells. However, little is understood about the regulation of NKT cells by negative costimulatory pathways. Here we show that PD-L1 and PD-1. but not PD-L2, are expressed on iNKT cells in spleen, liver and thymus. In vivo activation with α-GalCer lead to increased cytokine production and expansion of iNKT cells in the absence of the PD-L1 pathway. To study whether PD-L1 deficiency on NKT cells would affect antigen specific T cell responses we utilized CD8+ OT-1 OVA transgenic T cells. α-GalCer enhanced the expansion and cytokine production of OT-1 T cells after adoptive transfer into wild type recipients. However, this expansion was significantly augmented when OT-1 T cells were adoptively transferred into PD-L1-/- recipients. In a B16 melanoma metastasis model, there was an increased clearance of lung nodules when PD-L1-/- recipients were given dendritic cells loaded with α-GalCer and TRP-2 peptide. These data demonstrate that blocking PDL1:PD-1 interactions between NKT cells and cells of the adaptive immune system are important in mounting an effective anti-tumor immune response.
Interaction of CD103 with E-cadherin triggers CCR5 recruitment at the immunological synapse resulting in intratumoral retention of tumor-specific CTL (40.37)
Authors: MAMI-CHOUAIB Fathia , Le Floc'h Audrey , Jalil Abdelali , Combadière Christophe , Franciszkiewicz Katarzyna 
Published: January 2023

Abstract
We previously characterized two tumor-specific T-cell clones from PBL and tumor-infiltrating lymphocytes (TIL) of a lung cancer patient with identical TCR and similar lytic potential, but with different anti-tumor reactivity. We demonstrated that the interaction of alphaE(CD103)beta7 integrin, expressed on the TIL clone but not on the PBL counterpart, with the epithelial marker E-cadherin on human lung tumor cells, plays a crucial role in TCR-mediated cytotoxicity. In the present study we show that both TIL and PBL clones are able to migrate towards autologous tumor cells and that chemokine receptor CCR5 is involved in this process. Interestingly, adoptive transfer of the PBL clone in the cognate tumor engrafted in SCID-NOD mice and subsequent TCR engagement and TGF-β1 secretion triggers CD103 expression on T-cell surface and thus potentiation of anti-tumor cytotoxic activity. Furthermore, confocal microscopy analyses indicated that the interaction of αEβ7 integrin with E-cadherin, but not LFA-1 with ICAM-1, promotes CCR5 recruitment at the immunological synapse formed between TIL and tumor cells, leading to inhibition of T-cell sensitivity to CCL5 chemotactic gradient. Our results provide evidence for a role of tumor microenvironment in regulating anti-tumor CTL function and suggest a role of CD103 in intratumoral retention of tumor-specific T cells by a mechanism involving CCR5.
Cbl-b-deficiency in tumor-reactive CD8+ T cells improves efficacy and bypasses the requirement for IL-2 administration during adoptive therapy of progressive leukemia (40.38)
Authors: Stromnes Ingunn M. , Blattman Joseph N. , Tan Xiaoxia , Greenberg Philip D. 
Published: January 2023

Abstract
OBJECTIVE: We have examined if decreasing Cbl-b expression in tumor-reactive CD8 T cells used for adoptive immunotherapy of progressive leukemia can enhance efficacy and bypass the requirement for IL-2 administration.
METHODS: Mice expressing a transgenic receptor, TCRgag, which renders CD8 T cells reactive with FBL leukemia, were crossed with Cbl-b-deficient and CD28-deficient mice. TCRgag Cbl-b+/+ and Cbl-b-/- cells were tested for function and expanded in vitro prior to use in adoptive therapy.
RESULTS: Cbl-b-/- TCRgag cells exhibited a lower threshold for T cell activation, greater IL-2 production and enhanced proliferation, expansion and survival. The enhanced response of Cbl-b-/- TCRgag cells compared to Cbl-b+/+ cells in vitro revealed both IL-2-dependent and IL-2-independent effects. In vivo, adoptively transferred Cbl-b+/+ TCRgag CD8 T cells can only prevent lethal disease in mice bearing disseminated leukemia if low dose IL-2 is subsequently administered to promote proliferation and maintain cell survival. By contrast, Cbl-b-/- TCRgag cells cured mice independent of a requirement for IL-2 administration.
CONCLUSIONS: These results suggest that targeting Cbl-b in antigen-specific T cells may provide a strategy to enhance efficacy of CD8 T cell adoptive immunotherapy in humans with cancer.
Deletion of adenosine A2A receptors on CD8 T cells enhances their accumulation in tumors and tumor-draining lymph nodes, as well as their ability to control tumor outgrowth (40.6)
Authors: Vincent Isaah S , Linden Joel M , Engelhard Victor H 
Published: January 2023

Abstract
Previous work has demonstrated that ablation of adenosine A2A receptor (A2AR) expression in tumor-bearing mice enhances tumor control. However, it is not yet clear what cells and functions are influenced by A2AR signaling. Here we show that the ability of adoptively transferred OT-I CD8 T cells to control ovalbumin expressing B16 melanomas in A2aR+/+ recipients is enhanced if the A2AR gene is ablated in the OT-I cells. This demonstrates directly that the ability of CD8 T cells to control tumors is influenced by adenosine. To further understand the functions of CD8 T cells influenced by A2AR deletion, we examined the activation, proliferation, and survival of A2AR+/+ and A2AR-/- OT-I cells in tumors and tumor-draining lymph nodes (TDLN) after co-transfer. While activation and proliferation of both populations in TDLN was comparable, the accumulation of A2AR-/- cells in both TDLN and tumor was enhanced relative to A2AR+/+ cells. Preliminary data suggest that this is due to enhanced survival of A2AR-/- CD8 T cells in TDLN. This enhanced accumulation does not occur in the lymph nodes of mice immunized with bone marrow derived dendritic cells or Vaccinia virus, suggesting that it reflects alterations in the level of adenosine specifically in TDLN. We theorize that enhanced accumulation of A2AR-/- CD8 T cells is at least partially responsible for their increased ability to control tumors.
Support: NIH R01 CA78400, F31 CA130117
Pharmacodynamics, Pharmacokinetics, and Tolerability of a B-Cell Specific Antibody-Targeted Chemotherapeutic Agent, Anti-CD79b-MCC-DM1, in Cynomolgus Monkeys (41.12)
Authors: Williams Marna , Li Dongwei , Fuji Reina , Fuh Franklin , Prabhu Saileta , Zheng Bing , Elkins Kristi , Yu Shang-Fan , Chuh Josefa , Tan Christine , Hongo Jo-anne , Raab Helga , Young Judy , Ross Sarajane , Kozak Katherine , Eaton Dan , Spencer Susan , Poon Kirsten A. , Fielder Paul , Tibbitts Jay , Berry Karen , Manning William , Ramakrishnan Vanitha , Ebens Allen , Polson Andrew G. 
Published: January 2023

Abstract
Antibody-based therapeutic approaches have revolutionized the treatment of non-Hodgkin's lymphomas (NHL) as well as other hematological malignancies. However, a large variability in clinical response has been observed and patients with refractory or relapsed lymphomas have limited therapeutic options.

Antibody drug conjugates (ADC) may prove valuable in this respect. The B cell surface antigen, CD79b, is an attractive target for this approach as it is rapidly internalized upon antibody engagement and has an appropriate expression pattern, being expressed only on normal and malignant B-cells. Anti-CD79b-MCC-DM1 is an ADC consisting of a chimeric monoclonal anti-CD79b antibody, 10D10, conjugated via a thioether linker to a cytotoxic drug, DM1 (a potent tubulin polymerization inhibitor).
To investigate the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of 10D10-MCC-DM1 in nonhuman primates, we administered 10D10-MCC-DM1 or unconjugated antibody 10D10 to cynomolgus monkeys. 10D10-MCC-DM1 and 10D10 resulted in sustained depletion of B-cells and B cell subsets in blood, with more substantial depletion in the group given 10D10-MCC-DM1. These findings correlated well with the depletion of B-cells observed in lymphoid tissues (bone marrow, lymph nodes, and spleen). Both 10D10-MCC-DM1 and 10D10 were well tolerated. Taken together, these preclinical data suggest that targeting CD79b with ADCs may provide a safe and effective therapy for B-cell malignancies in humans.
Priming anti-tumor responses with MHC I single chain trimer vaccines (41.16)
Authors: Ordaz Maria L , Li Gang , Andreansky Samita , Lybarger Lonnie 
Published: January 2023

Abstract
The inefficiency of the MHC I presentation pathway and the low affinity of some tumor peptide/MHC complexes can lead to a reduced density of tumor-associated peptide/MHC complexes on tumor cells, which can partly explain the failure to prime CTL (cytotoxic T lymphocyte) responses against tumors. Here, we are evaluating a set of MHC I Single Chain Trimers (SCTs) used in conjunction with dendritic cell (DC) or DNA vaccination for their ability to prime a CTL response specific for tumor antigens. A SCT consists of an MHC I molecule covalently linked to a peptide and our goal is to test whether tumor-associated antigen presentation by MHC I SCTs will result in better CTL priming and immune protection than more conventional peptide-specific vaccination protocols. The melanoma antigenic peptide TRP2 (Tyrosinase related protein 2, aa180-188) was chosen in this study for presentation on Kb SCTs; OVA-SCT (Kb-SIINFEKL) was chosen as a control. In vivo experiments suggest that mice vaccinated with TRP2 SCT-transduced DCs present better tumor protection, compared to controls. SCT vaccines, combined with Treg depletion are in progress to evaluate specific priming and tumor protection.
Our preliminary data suggest that SCTs represent a promising technology capable of priming strong and specific CTL responses, with the potential of eliciting systemic tumor protection.
Supported by the Arizona Biomedical Research Commission.