ABSTRACT
Cutaneous 5T cell lymphoma (CTCL), characterized by malignant T cells infiltrating the skin with potential for dissemination, remains a challenging disease to diagnose and treat due to disease heterogeneity, treatment resistance, and lack of effective and standardized diagnostic and prognostic clinical tools. Currently, diagnosis of CTCL practically relies on clinical presentation, histopathology, and immunohistochemistry. These methods are collectively fraught with limitations in sensitivity and specificity. Fortunately, recent advances in flow cytometry, polymerase chain reaction, high throughput sequencing, and other molecular techniques have shown promise in improving diagnosis and treatment of CTCL. Examples of these advances include T cell receptor clonotyping via sequencing to detect CTCL earlier in the disease course and single-cell RNA sequencing to identify gene expression patterns that commonly drive CTCL pathogenesis. Experience with these techniques has afforded novel insights which may translate into enhanced diagnostic and therapeutic approaches for CTCL.
Subject(s)
Lymphoma, Non-Hodgkin , Lymphoma, T-Cell, Cutaneous , Skin Neoplasms , Humans , Lymphoma, T-Cell, Cutaneous/diagnosis , Lymphoma, T-Cell, Cutaneous/genetics , Lymphoma, T-Cell, Cutaneous/therapy , Skin , Disease Progression , Skin Neoplasms/diagnosis , Skin Neoplasms/genetics , Skin Neoplasms/therapyABSTRACT
Circulating memory CD8 T cell trafficking and protective capacity during liver-stage malaria infection remains undefined. We find that effector memory CD8 T cells (Tem) infiltrate the liver within 6 hours after malarial or bacterial infections and mediate pathogen clearance. Tem recruitment coincides with rapid transcriptional upregulation of inflammatory genes in Plasmodium-infected livers. Recruitment requires CD8 T cell-intrinsic LFA-1 expression and the presence of liver phagocytes. Rapid Tem liver infiltration is distinct from recruitment to other non-lymphoid tissues in that it occurs both in the absence of liver tissue resident memory "sensing-and-alarm" function and â¼42 hours earlier than in lung infection by influenza virus. These data demonstrate relevance for Tem in protection against malaria and provide generalizable mechanistic insights germane to control of liver infections.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunologic Memory , Liver/immunology , Malaria/immunology , Plasmodium berghei/immunology , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/microbiology , CD8-Positive T-Lymphocytes/parasitology , Disease Models, Animal , Female , Host-Parasite Interactions , Listeria monocytogenes/immunology , Listeria monocytogenes/pathogenicity , Listeriosis/blood , Listeriosis/immunology , Listeriosis/microbiology , Liver/metabolism , Liver/microbiology , Liver/parasitology , Lymphocyte Function-Associated Antigen-1/metabolism , Malaria/blood , Malaria/parasitology , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Parasite Load , Phagocytes/immunology , Phagocytes/metabolism , Phagocytes/microbiology , Phagocytes/parasitology , Plasmodium berghei/pathogenicity , Time FactorsABSTRACT
Radiation-attenuated sporozoite (RAS) vaccination offers hope for global malaria control through induction of protective liver-stage-specific memory CD8 T cells. Effective RAS vaccination regimens exist; however, widespread implementation remains unfeasible. A key difficulty resides in the need to administer three or more doses i.v. to achieve sufficient immunity. Strategies to reduce the number of RAS doses are therefore desirable. Here we used mice to model human immune responses to a single, suboptimal weight-normalized RAS dose administered i.v. followed by subunit vaccination to amplify liver-stage-specific memory CD8 T cells. RAS+subunit prime-boost regimens increased the numbers of liver-stage-specific memory CD8 T cells to a level greater than is present after one RAS vaccination. Both i.v. and i.m. subunit vaccine delivery induced immunity in mice, and many vaccinated mice completely cleared liver infection. These findings are particularly relevant to human vaccine development because RAS+subunit prime-boost vaccination would reduce the logistical challenges of multiple RAS-only immunizations.
Subject(s)
Liver Diseases/immunology , Malaria Vaccines/immunology , Malaria/immunology , Sporozoites/immunology , Vaccines, Attenuated/immunology , Vaccines, Subunit/immunology , Animals , Immunization , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , VaccinationSubject(s)
Malaria, Falciparum , Plasmodium falciparum , Homicide , Humans , Phagocytosis , T-LymphocytesSubject(s)
Flow Cytometry/methods , Fluorescence Resonance Energy Transfer/methods , Fluorescent Dyes/metabolism , Reactive Oxygen Species/metabolism , Animals , Benzothiazoles/chemistry , Benzothiazoles/metabolism , Carbocyanines/chemistry , Carbocyanines/metabolism , Fluorescent Dyes/chemistry , Granulocytes/chemistry , Granulocytes/metabolism , Humans , Mercaptoethanol/chemistry , Mercaptoethanol/metabolism , Phycocyanin/chemistry , Phycocyanin/metabolism , Reproducibility of ResultsABSTRACT
Each year over 200 million malaria infections occur, with over 400 000 associated deaths. Vaccines formed with attenuated whole parasites can induce protective memory CD8 T cell responses against liver-stage malaria; however, widespread administration of such vaccines is logistically challenging. Recent scientific findings are delineating how protective memory CD8 T cell populations are primed and maintained and how such cells mediate immunity to liver-stage malaria. Memory CD8 T cell anatomic localization and expression of transcription factors, homing receptors, and signaling molecules appear to play integral roles in protective immunity to liver-stage malaria. Further investigation of how such factors contribute to optimal protective memory CD8 T cell generation and maintenance in humans will inform efforts for improved vaccines.
