Anticancer immunotherapies transition postcapillary venules into high-endothelial venules that generate TCF1+ T lymphocyte niches through a feed-forward loop

The lack of T-cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLS), which are the local site of humoral and cellular immune responses against cancers, are associated with good prognosis and have recently been detected in Immune Checkpoint Blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing scRNA sequencing, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke the transition of postcapillary venules into inflamed high endothelial venules (HEVs), which generate permissive TA-TLS-like lymphocyte niches with PD1neg and PD1+TCF1+CD8 T cell progenitors that differentiate into GrzB+TCF1neg TIM3+ PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived lymphotoxin signals revealing that tumor-HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

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Single-cell immune profiling of matched disease and recovery phase blood of COVID-19 patients reveals anti-LAG3 based immune checkpoint therapy as a promising option

10.21203/rs.3.rs-24576/v1 ◽

2020 ◽

Author(s):

Qing Xiong ◽

Cheng Peng ◽

Xiaomin Yan ◽

Lin Chen ◽

Xueqi Yan ◽

...

Keyword(s):

T Cell ◽

Single Cell ◽

Immune Checkpoint ◽

Dominant Role ◽

Recovery Phase ◽

Immune Checkpoint Blockade ◽

Effector Memory ◽

Effector Cells ◽

T Effector Cells ◽

Inhibitory Molecules

Abstract We profiled the circulating immune cells in COVID-19 patients during the active disease and recovery phases via single cell RNA, TCR and BCR sequencing in order to elucidate the key anti-virus adaptive immune responses, and explore potential immunomodulatory therapeutic strategies. T cell competence plays a dominant role in anti-SARS-CoV-2 immunity. Clonally expanded CD4 T effector cells averted CD8 T cell exhaustion, and expansion of multiple CD8 T effector/memory clones was correlated with rapid virus clearance. In contrast, the patients lacking CD4 TEFF cell clonal expansion harbored exhausted CD8 TEFF cells co-expressing multiple co-inhibitory molecules. In addition, more than 90% of the exhausted cells expressed at least 2 and more than half of exhausted cells expressed at least 4 inhibitory molecules. Furthermore, co-expression of LAG3, Galectin-9, and SLAMF6 is the inhibitory molecule expression signature of exhausted T cell population in SARS-CoV-2 infection. Our findings indicate that LAG3-based immune checkpoint blockade is a promising strategy for treating COVID-19.

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CRISPR-Cas9–Mediated TIM3 Knockout in Human Natural Killer Cells Enhances Growth Inhibitory Effects on Human Glioma Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22073489 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3489

Author(s):

Takayuki Morimoto ◽

Tsutomu Nakazawa ◽

Ryosuke Matsuda ◽

Fumihiko Nishimura ◽

Mitsutoshi Nakamura ◽

...

Keyword(s):

T Cell ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Protein Complexes ◽

Lymphocyte Activation ◽

Exon 2 ◽

Effector Cells ◽

Guide Rna ◽

Human Natural Killer Cells

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Natural Killer (NK) cells are potent cytotoxic effector cells against tumor cells inducing GBM cells; therefore, NK cell based- immunotherapy might be a promising target in GBM. T cell immunoglobulin mucin family member 3 (TIM3), a receptor expressed on NK cells, has been suggested as a marker of dysfunctional NK cells. We established TIM3 knockout in NK cells, using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9). Electroporating of TIM3 exon 2- or exon 5-targeting guide RNA- Cas9 protein complexes (RNPs) inhibited TIM3 expression on NK cells with varying efficacy. T7 endonuclease I mutation detection assays showed that both RNPs disrupted the intended genome sites. The expression of other checkpoint receptors, i.e., programmed cell death 1 (PD1), Lymphocyte-activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and TACTILE (CD96) were unchanged on the TIM3 knockout NK cells. Real time cell growth assays revealed that TIM3 knockout enhanced NK cell–mediated growth inhibition of GBM cells. These results demonstrated that TIM3 knockout enhanced human NK cell mediated cytotoxicity on GBM cells. Future, CRISPR-Cas9 mediated TIM3 knockout in NK cells may prove to be a promising immunotherapeutic alternative in patient with GBM.

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Phase 2 Study of Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy of Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v130.suppl_1.815.815 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 815-815

Author(s):

Farhad Ravandi ◽

Naval Daver ◽

Guillermo Garcia-Manero ◽

Christopher B Benton ◽

Philip A Thompson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Myeloid Leukemia ◽

Research Funding ◽

T Cell Subsets ◽

Newly Diagnosed ◽

Effector Cells ◽

T Effector Cells ◽

Grade 3

Abstract Background: Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses by enabling T-cells in murine models of AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells are increased in bone marrow (BM) of pts with AML (Daver et al, AACR 2016). PD1 inhibition has shown activity in AML (Berger et al, Clin Cancer Res 2008). We hypothesized that addition of nivolumab to an induction regimen of ara-C and idarubicin may prolong relapse-free survival (RFS) and overall survival (OS); this study was designed to determine the feasibility of this combination. Methods: Pts with newly diagnosed acute myeloid leukemia (by WHO criteria; ≥20% blasts) and high risk MDS (≥10% blasts) were eligible to participate if they were 18-65 yrs of age and had adequate performance status (ECOG ≤3) and organ function (LVEF ≥ 50%; creatinine ≤ 1.5 g mg/dL, bilirubin ≤ 1.5 mg/dL and transaminases ≤ 2.5 times upper limit of normal). Treatment included 1 or 2 induction cycles of ara-C 1.5 g/m2 over 24 hours (days 1-4) and Idarubicin 12 mg/m2 (days 1-3). Nivolumab 3 mg/kg was started on day 24 ± 2 days and was continued every 2 weeks for up to a year. For pts achieving complete response (CR) or CR with incomplete count recovery (CRi) up to 5 consolidation cycles of attenuated dose ara-C and idarubicin was administered at approximately monthly intervals. Eligible pts received an allogeneic stem cell transplant (alloSCT) at any time during the consolidation or thereafter. Results: 3 pts with relapsed AML were treated at a run-in phase with a dose of nivolumab 1 mg/kg without specific drug-related toxicity. Subsequently, 32 pts (median age 53 yrs; range, 26-65) were treated as above including 30 with AML (24 de novo AML, 2 therapy-related AML, 3 secondary AML and 1 therapy-related secondary AML) and 2 high risk MDS. Pre-treatment genetic risk by ELN criteria was 11 adverse, 16 intermediate, and 5 favorable, including 2 FLT3 -ITD mutated, 5 NPM1 mutated, and 7 TP53 mutated. All 32 pts were evaluable for response and 23 (72%) achieved CR/CRi (19 CR, 4 CRi). The 4-week and 8 week mortality was 6% and 6%. The median number of doses of nivolumab received was 6 (range, 0-13); one pt did not receive nivolumab due to insurance issues. 9 pts underwent an alloSCT. After a median follow-up of 8.3 mths (range, 1.5-17.0) the median RFS among the responding pts has not been reached (range, 0.1 - 15.8 mths) and the median OS has not been reached (range 0.5-17.0 mths). Grade 3/4 immune mediated toxicities have been observed in 5 pts and include rash, pancreatitis, and colitis. Other grade 3/4 toxicities thought to be potentially related to nivolumab include cholecystitis in one pt. 9 pts proceeded to an alloSCT. Donor source was matched related in 2, matched unrelated in 6 and haplo-identical in 1 pt. Conditioning regimen was Fludarabine plus busulfan-based in 8, and fludarabine plus melphalan in 1 pt. 4 pts developed graft versus host disease (GVHD)(grade I/II in 3, grade III/IV in 1), which responded to treatment in 3. Multicolor flow-cytometry studies are conducted by the Immunotherapy Platform on baseline (prior to first dose of nivolumab) and on-treatment BM aspirate and peripheral blood to assess the T-cell repertoire and expression of co-stimulatory receptors and ligands on T-cell subsets and leukemic blasts, respectively. The baseline BM was evaluated on 23 of the 32 evaluable pts, including 18 responders and 5 non-responders. Pts who achieved a CR/CRi had a trend of higher frequency of live CD3+ total T cell infiltrate as compared to non-responders in the baseline BM aspirates (Fig 1A). We evaluated expression of immune markers on T cell subsets: CD4 T effector cells [Teff]: CD3+CD4+CD127lo/+Foxp3-, CD4 T regulatory cells [Treg]: CD3+CD4+CD127-Foxp3+, and CD8 T cells. At baseline, BM of non-responders had significantly higher percentage of CD4 T effector cells co-expressing the inhibitory markers PD1 and TIM3 (p<0.05) and a trend towards higher percentage of CD4 T effector cells co-expressing PD1 and LAG3 compared to responders (Fig 1B). Co-expression of TIM3 or LAG3 on PD1+ T cells have been shown to be associated with an exhausted immune phenotype in AML (Zhou et al., Blood 2011). Conclusion: Addition of nivolumab to ara-C and anthracycline induction chemotherapy is feasible and safe in younger pts with AML. Among the pts proceeding to alloSCT the risk of GVHD is not significantly increased. Figure 1 Figure 1. Disclosures Daver: Pfizer Inc.: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kiromic: Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Incyte Corporation: Honoraria, Research Funding. Thompson: Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jabbour: Bristol-Myers Squibb: Consultancy. Takahashi: Symbio Pharmaceuticals: Consultancy. DiNardo: Novartis: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sharma: Jounce: Consultancy, Other: stock, Patents & Royalties: Patent licensed to Jounce; Astellas: Consultancy; EMD Serono: Consultancy; Amgen: Consultancy; Astra Zeneca: Consultancy; GSK: Consultancy; Consetellation: Other: stock; Evelo: Consultancy, Other: stock; Neon: Consultancy, Other: stock; Kite Pharma: Consultancy, Other: stock; BMS: Consultancy. Cortes: BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding. Kantarjian: Delta-Fly Pharma: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding.

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Regulation of T cell expansion by antigen presentation dynamics

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812800116 ◽

2019 ◽

Vol 116 (13) ◽

pp. 5914-5919 ◽

Cited By ~ 15

Author(s):

Andreas Mayer ◽

Yaojun Zhang ◽

Alan S. Perelson ◽

Ned S. Wingreen

Keyword(s):

T Cells ◽

T Cell ◽

Cell Expansion ◽

Essential Feature ◽

Adaptive Immune Response ◽

Adaptive Immune System ◽

Effective Response ◽

Effector Cells ◽

Adaptive Immune ◽

T Cell Expansion

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher-affinity clones can suppress the proliferation of lower-affinity clones, thereby promoting the specificity of the response. Using the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.

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Effective Prevention of Acute Graft-Verses-Host Disease by Targeting PKC Alpha and PKC Theta in Mice

Blood ◽

10.1182/blood.v118.21.1898.1898 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1898-1898

Author(s):

Kelley M.K. Haarberg ◽

Crystina Bronk ◽

Dapeng Wang ◽

Amer Beg ◽

Xue-Zhong Yu

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Acute Gvhd ◽

T Cell Signaling ◽

Effector Cells ◽

T Effector Cells ◽

Immunologic Synapse

Abstract Abstract 1898 Protein kinase C theta (PKCθ), a T cell signaling molecule, has been implicated as a therapeutic target for several autoimmune diseases as well as graft-versus-host disease (GVHD). PKCθ plays a vital role in stabilization of the immunologic synapse between T effector cells and antigen presenting cells (APC), but has been shown to be excluded from the immunologic synapse in T regulatory cells (T reg). PKCθ inhibition reduces the alloreactivity of donor T cells responsible for induction of GVHD while preserving graft-versus-leukemia (GVL) responses. The roles of PKCθ and the potential compensatory alpha isoform (PKCα) are not clearly defined with regard to alloresponses or T cell mediated responses in GVHD. In this context, we measured PKCθ and PKCα/θ gene deficient T cell activation upon TCR-ligation in vitro using [3H]-TdR incorporation and CSFE labeling assays. T cells from PKCθ and PKCα/θ gene deficient donor mice were utilized in vivo in a pre-clinical allogenic murine model of myeloablative bone marrow transplantation (BMT). The development of GVHD was monitored in recipient mice with or without injection of A20-luciferase cells to observe the progression of GVL in vivo. Combined blockade of PKCα and PKCθ causes a significant decrease in T cell proliferation compared to blocking PKCθ alone in vitro. Deficiency in PKCα and PKCθ had no effect on immune reconstitution following irradiation and BMT in vivo. Even with a high transplant load of 5×106 CD4+ and CD8+ T cells, PKCα/θ deficient (PKCα/θ−/−) T cells failed to induce acute GVHD. Our data suggest that the ability of double deficient T cells to induce GVHD was further reduced than PKCθ-deficient T cells. Additionally, a greater number and percentage of B220+ B cells and FoxP3+ T regs were isolated from the spleens of PKCα/θ−/− T cell recipient mice 120 after BMT than were isolated from wild type (WT) or PKCθ−/− T cell recipients. Fewer CD4+ or CD8+ T effector cells were isolated from the spleens of PKCα/θ−/− T cell recipient mice 120 after BMT than were isolated from wild type or PKCθ−/− T cell recipients. Importantly, the activity of B cells isolated from PKCα/θ−/− T cell recipient mice 120 after BMT was greater on a per cell basis, while the activity of T effector cells isolated from these mice was greatly reduced compared to WT or PKCθ−/− T cell recipients. While not absent, GVL was reduced in PKCα/θ−/− T cell recipient mice when compared to WT or PKCθ−/− T cell recipients. This work demonstrates the requirement of PKCα and θ for optimal activation and function of T cells in vitro. These experiments highlight a potential compensatory role for PKCα in the absence of PKCθ in T cell signaling and activation. Combined deficiency of PKCα and θ prevents induction of acute GVHD while improving the maintenance of splenic cellularity in PKCα/θ T cell recipient mice. Additionally, PKCα/θ dual deficient T cell transplant shifts the splenic balance toward a greater number and percentage of T reg and B cells and away from T effector cells following BMT. The reduced and sub-optimally active T effector cells isolated from PKCα/θ−/− T cell recipient mice in combination with reduced GVL stresses the importance of PKCα and θ molecules and their roles in T cell activity in the context of both GVHD and GVL. Dual deficiency of PKCα/θ is associated with a decline of T effector function that is optimal for the amelioration of GVHD, but is perhaps too reduced to substantially maintain effective GVL. Modulation of PKCα and θ signaling presents a valid avenue of investigation as a therapeutic option for GVHD. Disclosures: No relevant conflicts of interest to declare.

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Immunosuppressive FVIII-Specific Human Cartregs in Hemophilia a

Blood ◽

10.1182/blood.v126.23.291.291 ◽

2015 ◽

Vol 126 (23) ◽

pp. 291-291 ◽

Cited By ~ 1

Author(s):

Jeong Heon Yoon ◽

Anja Schmidt ◽

Yong Chan Kim ◽

Christoph Koenigs ◽

David William Scott

Keyword(s):

T Cells ◽

T Cell ◽

Hemophilia A ◽

Cell Clone ◽

Coagulation Factor ◽

Specific Staining ◽

Promising Alternative ◽

Effector Cells ◽

T Effector Cells ◽

T Cell Clone

Abstract Hemophilia A is an X-linked disorder, in which mutations in the coagulation Factor VIII (FVIII) gene lead to a loss of FVIII function and serious bleeding episodes. These episodes can be treated with recombinant FVIII protein replacement. Unfortunately, ~25% of hemophilia A patients produce inhibitory anti-FVIII antibodies because of lack of tolerance. Thus, it is necessary to develop effective tolerogenic therapies to prevent, as well as reverse, inhibitor formation. Previously, we generated engineered antigen-specific regulatory T cells (Tregs), created by transduction of a recombinant T-cell receptor (TCR) isolated from a hemophilia A subject's T cell clone. The resulting engineered T cells bind MHC tetramers, proliferate in response to a specific FVIII epitope, and suppress effector responses to FVIII. In this study, we engineered a FVIII-specific chimeric antigen receptor (ANS8CAR) using a FVIII-specific scFv derived from a synthetic phage display library. Following initial experiments in naïve CD4 T cells, this CAR was introduced into human Tregs. Western blot and specific staining with FVIII verified CAR expression. Transduced ANS8CAR Tregs proliferated in response to FVIII and were able to suppress the proliferation of FVIII-specific T effector cells in vitro. Additionally, the proliferation of T effector cells with different FVIII domain specificity was suppressed as well when ANS8CAR-transduced Tregs were activated with FVIII. Thus, engineered cells are able to promote bystander suppression. Cytokine expression of ANS8CAR-transduced Tregs was comparable to expression of untransduced and TCR-transduced Tregs indicating that the regulatory phenotype of Tregs was not negatively influenced by ANS8CAR expression. In conclusion, CAR-transduced Tregs seem to be a promising alternative to TCR-transduced Tregs for a future tolerogenic treatment of hemophilia A patients with inhibitory FVIII-specific antibodies. Supported by NIH grants HL061883 and HL126727 (DWS), the Society of Thrombosis and Hemostasis Research, and the Günter Landbeck Excellence Award (AS). Disclosures Kim: Henry Jackson Foundation: Other: patent filed. Scott:Henry Jackson Foundation: Other: patent filed.

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Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma

Journal of Experimental Medicine ◽

10.1084/jem.20080099 ◽

2008 ◽

Vol 205 (9) ◽

pp. 2125-2138 ◽

Cited By ~ 146

Author(s):

Sergio A. Quezada ◽

Karl S. Peggs ◽

Tyler R. Simpson ◽

Yuelei Shen ◽

Dan R. Littman ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Clinical Results ◽

Tumor Rejection ◽

Cell Depletion ◽

Effector Cells ◽

T Effector Cells ◽

Melanoma Model

Interference with inhibitory immunological checkpoints controlling T cell activation provides new opportunities to augment cancer immunotherapies. Whereas cytotoxic T lymphocyte–associated antigen-4 blockade has shown promising preclinical and clinical results, therapeutic CD4+CD25+ T reg cell depletion has failed to consistently enhance immune-based therapies. Using B16/BL6, a transplantable murine melanoma model, we show a dichotomy between the effects of T reg cell depletion on tumor rejection dependent on whether depletion occurs before (prophylactic) or after (therapeutic) tumor engraftment. Failure to promote rejection with therapeutic depletion is not related to lack of T reg cell depletion, to elimination of CD25+ effector T cells, or to a failure to enhance systemic antitumor T cell responses, but correlates with failure of effector cells to infiltrate the tumor and increase the intratumor ratio of effector T cell/T reg cell. Finally, systemic antitumor responses generated upon therapeutic T reg cell depletion are significantly stronger than those generated in the presence of T reg cells, and are capable of eliciting rejection of established tumors after transfer into immunoablated recipients receiving combination immunotherapy. The data demonstrate a dissociation between measurable systemic responses and tumor rejection during CD25-directed T reg cell depletion, and suggest an alternative, clinically applicable strategy for the treatment of established tumors.

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B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

10.1101/478735 ◽

2018 ◽

Author(s):

Johannes Griss ◽

Wolfgang Bauer ◽

Christine Wagner ◽

Margarita Maurer-Granofszky ◽

Martin Simon ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Immune Checkpoint ◽

Cd8 T Cell ◽

Immune Checkpoint Blockade ◽

Human Melanoma ◽

Checkpoint Blockade ◽

Inflammatory Factors ◽

T Effector Cells

Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Established mechanisms that underlie therapy response and resistance center on anti-tumor T cell responses. Here we show that tumor-associated B cells are vital to tumor associated inflammation. Autologous B cells were directly induced by melanoma conditioned medium, expressed pro- and anti-inflammatory factors, and differentiated towards a plasmablast-like phenotype in vitro. We could identify this phenotype as a distinct cluster of B cells in an independent public single-cell RNA-seq dataset from melanoma tumors. There, plasmablast-like tumor-associated B cells showed expression of CD8+T cell-recruiting chemokines such as CCL3, CCL4, CCL5 and CCL28. Depletion of tumor associated B cells in metastatic melanoma patients by anti-CD20 immunotherapy decreased overall inflammation and CD8+T cell numbers in the human melanoma TME. Conversely, the frequency of plasmablast-like B cells in pretherapy melanoma samples predicted response and survival to immune checkpoint blockade in two independent cohorts. Tumor-associated B cells therefore orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and may represent a predictor for response and survival to immune checkpoint blockade in human melanoma.

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Transcriptomic profiling of plaque psoriasis and cutaneous T cell subsets during treatment with secukinumab

10.1101/764118 ◽

2019 ◽

Author(s):

Jared Liu ◽

Hsin-Wen Chang ◽

Kristen M. Beck ◽

Sahil Sekhon ◽

Timothy H. Schmidt ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Plaque Psoriasis ◽

Immune Cell ◽

T Cell Subsets ◽

Skin Tissue ◽

Rapid Reduction ◽

Effector Cells ◽

Lesional Skin ◽

T Effector Cells

AbstractThe IL17A inhibitor secukinumab is efficacious for the treatment of psoriasis. In order to define its mechanism of action, it is important to understand its impact on psoriatic whole skin tissue as well as specific skin-resident immune cell populations such as T lymphocytes. In this study, we treated 15 moderate-to-severe plaque psoriasis patients with secukinumab and characterized the longitudinal transcriptomic changes of whole lesional skin tissue and cutaneous CD4+ T effector cells (Teffs), CD4+ T regulatory cells (Tregs), and CD8+ T effector cells during 12 weeks of treatment. Secukinumab was clinically effective, with 100%, 47%, and 27% of patients in the study achieving PASI75, PASI90, and PASI100 by week 12, respectively. At baseline prior to treatment, we observed that IL17A overexpression predominates in psoriatic CD8+ T cells rather than Teffs, supporting the importance of IL-17-secreting CD8+ T cells (Tc17) compared to IL-17-secreting CD4+ T cells (Th17) cells in the pathogenesis of psoriasis. Although secukinumab targets only IL17A, we observed rapid reduction of IL17A, IL17F, IL23A, IL23R, and IFNG expression in lesional skin as soon as 2 weeks after initiation of treatment and normalization of expression by week 12. Secukinumab treatment resulted in resolution of 89-97% of psoriasis-associated expression differences in both bulk tissue and T cell subsets by week 12 of treatment. Overall, secukinumab appears to rapidly reverse many of the molecular hallmarks of psoriasis.

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Regulation of T cell expansion by antigen presentation dynamics

10.1101/377036 ◽

2018 ◽

Author(s):

Andreas Mayer ◽

Yaojun Zhang ◽

Alan S. Perelson ◽

Ned S. Wingreen

Keyword(s):

T Cells ◽

T Cell ◽

Cell Expansion ◽

Essential Feature ◽

Adaptive Immune Response ◽

Adaptive Immune System ◽

Effective Response ◽

Effector Cells ◽

Adaptive Immune ◽

T Cell Expansion

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher affinity clones can suppress the proliferation of lower affinity clones, thereby promoting the specificity of the response. Employing the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.

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