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In this Q&A, Cell Press Community Review Scientific Editor Leia Judge talks to Dr. Clint Allen and Dr. Sandro Santagata about their new papers "Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer" and "Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma" and their experiences with publishing through Cell Press Community Review. [ABSTRACT FROM AUTHOR]

Discrete tissue niches are emerging as essential prerequisites enabling cell communication and function in both homeostasis and disease. In a recent Cell paper, Di Pilato et al. identify a unique dendritic cell-cytotoxic T cell crosstalk within the perivascular space that facilitates T cell survival and proliferation and drives anti-tumor activity. [ABSTRACT FROM AUTHOR]

Presentation of exogenous antigens loaded on major histocompatibility complex class I molecules by antigen presenting cells, termed cross-presentation, is essential for the induction of CD8+ T cells and is performed mainly by specialized dendritic cell subsets. Research into this field has described two main mechanisms of cross-presentation, the cytosolic pathway and the vacuolar pathway. As the first step in cross-presentation, surface receptors relating to cross-presentation are required in the recognition and uptake of Ags, which include C-type lectin receptors, immunoglobulin γ Fc region receptor, chemokine receptor, scavenger receptor etc. After uptake by the cells, there are also many molecules that enable Ags to participate in cross-presentation pathways. By this approach, exogenous Ags can induce CD8+ T cells into cytotoxic T lymphocytes, which is of great significance to induce antitumor and antiviral immune responses, and the molecular mechanism would facilitate the development of related adjuvants. However, the detailed mechanisms of cross-presentation still remain unknown. In this paper, some latest researches, including two major pathways, DC surface receptors and application prospects are summarized. [ABSTRACT FROM AUTHOR]

Malaria is a life-threatening disease caused by infection with Plasmodium parasites. The goal of developing an effective malaria vaccine is yet to be reached despite decades of massive research efforts. CD4+ helper T cells, CD8+ cytotoxic T cells, and γδ T cells are associated with immune responses to both liver-stage and blood-stage Plasmodium infection. The immune responses of T cell-lineages to Plasmodium infection are associated with both protection and immunopathology. Studies with mouse model of malaria contribute to our understanding of host immune response. In this paper, we focus primarily on mouse malaria model with blood-stage Plasmodium berghei infection and review our knowledge of T cell immune responses against Plasmodium infection. Moreover, we also discuss findings of experimental human studies. Uncovering the precise mechanisms of T cell-mediated immunity to Plasmodium infection can be accomplished through further investigations using mouse models of malaria with rodent Plasmodium parasites. Those findings would be invaluable to advance the efforts for development of an effective malaria vaccine. [ABSTRACT FROM AUTHOR]

In this paper, we consider the combined effects of cytotoxic T lymphocyte (CTL) responses on the competition dynamics of two Simian immunodeficiency virus (SIV) strains model. One of strains concerns a relatively slowly replicating and mildly cytopathic virus in the early infection (SIVMneCL8), the other is faster replicating and more cytopathic virus at later stages of the infection (SIVMne170). It is shown that the global dynamics of the ordinary differential equations can be determined by several threshold parameters, and we prove the global stability of the equilibria by rigorous mathematical analysis. To account for a series of infection mechanism leading to viral production, we incorporate time delays in the infection term. Using the methods of constructing suitable Lyapunov functionals and LaSalle’s invariance principle, we obtain the sufficient conditions for the global attractiveness of infection-free equilibrium with both virus strains going extinct, single-infection equilibrium with one of two virus strains out-competing the other one and the two strains coexisting infection equilibrium. We establish that the intracellular delays can destabilize the single-infection equilibrium leading to Hopf bifurcation and periodic oscillations. We show that introduction of immune responses is responsible for the coexistence of two virus strains and the intracellular delays may alter the two-strain competition results. Numerical simulations are presented to illustrate the theoretical conclusions. [ABSTRACT FROM AUTHOR]

• Major immune effector cells like CD8+ T lymphocytes and natural killer cells are able to kill or inhibit Hepatocellular carcinoma (HCC) cells and their cytotoxic ability can be enhanced or down-regulated by certain cytokines or drugs. • HCC cells can impair the function of major immune effector cells through a variety of mechanisms. • Organoids or direct contact cell co-culture especially with primary HCC cells and tumor infiltrating lymphocytes provide better understanding of cell–cell interactions between major immune effector cells and HCC cells. • Immunotherapy like checkpoint inhibitors and adoptive cell transfer showed notable effectiveness and safety in preventing HCC recurrence as adjuvant therapy. Hepatocellular carcinoma (HCC) is the most common liver neoplasm with high morbidity and mortality. Tumor immunotherapy might be promising adjuvant therapy for HCC after surgery. To better develop HCC immunotherapy, comprehensive understanding of cell–cell interactions between immune effector cells and HCC cells remains crucial. To review the existing studies to summarize the cell–cell interactions between major immune effector cells and HCC cells providing new data for HCC immunotherapy. A systematic review was conducted by searching PubMed database covering all papers published in recent five years up to January 2020. The guidelines of the preferred reporting items for systematic reviews were firmly followed. There are 9 studies researching the interactions between CD8+ T lymphocytes and HCC cells and 22 studies researching that between natural killer (NK) cells and HCC cells. Among the 9 studies, 6 studies reported that CD8+ T lymphocytes showed cytotoxicity towards HCC cells while 3 studies found CD8+ T lymphocytes were impaired by HCC cells. Among the 22 studies, 20 studies presented that NK cells could inhibit HCC cells. Two studies were found to report NK cell dysfunction in HCC. Based on the systematic analysis, we concluded that CD8+ T lymphocytes and NK cells can inhibit HCC cells. While in turn, HCC cells can also result in the dysfunction of those effector cells through various mechanisms. Organoids and direct contact cell co-culture with primary HCC cells and TILs should be the most innovative way to investigate the interactions and develop novel immunotherapy. [ABSTRACT FROM AUTHOR]

Patients who fail to adequately reconstitute the donor-derived immune system after allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for infections and leukemia relapse. In the past, pan T-cell depleted haploidentical grafts were associated with delayed immune reconstitution (IR). Recently, the majority of patients receiving αβ T-cell/B-cell depleted haploidentical HSCT (αβhaplo-HSCT) reach a threshold of 200 CD3+ T cells/mcl by 100 days after HSCT (Bertaina A et al. Blood 2014 Jul 31;124(5):822-6). However, a proportion of patients experience a slower IR with consequent higher morbidity and mortality. Early prediction of delayed IR may permit prompt clinical intervention such as infusion of donor lymphocytes or of virus-specific cytotoxic T cells. Flow cytometry, the most widely applied approach for IR analysis, suffers from intrinsic limitations, such as high lymphocyte number requirement, degradation of samples, and insufficient standardization due to technical and operator variability. To overcome these limitations, we used a DNA methylation-based quantitative PCR that detects the epigenetic signature of different peripheral blood immune cell subsets (epigenetic quantification). This technique provides relative and absolute immune cell counts applicable to fresh, frozen, or paper-spotted dried blood. Epigenetic measurements are based on a per cell DNA copy number and provide a clear positive or negative signal rather than arbitrarily defined thresholds for "positivity" as in flow cytometry. We hypothesize that epigenetic quantification at day 15 after αβhaplo-HSCT could predict flow-based IR at day 100. Patients were consented at Lucile Packard Children's Hospital (Stanford, CA). Blood was collected between days 10-17 for epigenetic quantification and days 82-124 for flow cytometry. Bisulfite treated DNA underwent qPCR quantification of cell type-specific DNA regions of de-methylation (Baron U et al. Sci Transl Med 2018 Aug 1;10(452):eaan3508). Flow cytometry was performed using directly conjugated antibodies. Absolute cell counts were determined, plotted, and then analyzed using a linear regression model. In the first 5 αβhaplo-HSCT patients evaluated, we found a direct correlation between the epigenetic quantification at day 15 and flow cytometry at day 100 for CD4+ T cells (P=0.01), while the early epigenetic quantification of CD3+ and CD8+ T cells was not informative (Fig. 1). Preliminary data suggest that the use of epigenetic quantification early after αβhaplo-HSCT can predict the IR of CD4+ T cells at day 100 in αβhaplo-HSCT recipients. Ongoing analysis on a larger cohort of both αβhaplo-HSCT and unmanipulated HSCT recipients, will confirm if epigenetic quantification results obtained early post-HSCT can be used as a clinical biomarker of delayed IR and guide physicians in the use of post-HSCT adoptive immunotherapy. [ABSTRACT FROM AUTHOR]