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Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease.

ABSTRACT: CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine ?-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and ?-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of ?-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and eomesodermin (Eomes). This effector population is predominately found in peripheral blood and is limited in LNs regardless of HIV infection or treatment status. As a result, CD4+ T cells generally lack effector functions in LNs, including cytolytic capacity and IFN? and ?-chemokine expression, even in HIV elite controllers and during acute/early HIV infection. While we do find the presence of degranulating CD4+ T cells in LNs, these cells do not bear functional or transcriptional effector T cell properties and are inherently poor to form stable immunological synapses compared to their peripheral blood counterparts. We demonstrate that CD4+ T cell cytolytic function, phenotype, and programming in the peripheral blood is dissociated from those characteristics found in lymphoid tissues. Together, these data challenge our current models based on blood and suggest spatially and temporally dissociated mechanisms of viral control in lymphoid tissues.

SUBMITTER: Buggert M

PROVIDER: S-EPMC5919077 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease.

Buggert Marcus M Nguyen Son S McLane Laura M LM Steblyanko Maria M Anikeeva Nadia N Paquin-Proulx Dominic D Del Rio Estrada Perla M PM Ablanedo-Terrazas Yuria Y Noyan Kajsa K Reuter Morgan A MA Demers Korey K Sandberg Johan K JK Eller Michael A MA Streeck Hendrik H Jansson Marianne M Nowak Piotr P Sönnerborg Anders A Canaday David H DH Naji Ali A Wherry E John EJ Robb Merlin L ML Deeks Steven G SG Reyes-Teran Gustavo G Sykulev Yuri Y Karlsson Annika C AC Betts Michael R MR

PLoS pathogens 20180413 4

CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine β-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and β-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report t ...[more]

PMID: 29652923

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Project description:UnlabelledCD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcriptional signature compared to Th1 CD4+ cells but shared similar features with HIV-specific cytolytic CD8+ T cells. Furthermore, HIV-specific cytolytic CD4+ T cells showed comparable killing activity relative to HIV-specific CD8+ T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4+ T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4+ T cells as an independent subset distinct from Th1 cells that show combined activity with CD8+ T cells in the long-term control of HIV infection.ImportanceThe ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8+ T cells to control the virus, while CD4+ T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4+ T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4+ T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8+ T cells. These findings are important for our understanding of HIV immunopathology.

Dataset Information

Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease.

Publications

Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease.

Similar Datasets

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