Blood T-cell receptor diversity decreases during the course of HIV infection, but the potential for a diverse repertoire persists

Baum, Paul; Young, J. R.; Schmidt, David J.; Zhang, Qianjun; Hoh, Rebecca; Busch, Michael P.; Martin, Jeffrey N.; Deeks, Steven G.; McCune, Joseph M.

doi:10.1182/blood-2011-11-395384

Cited by 37 publications

(42 citation statements)

References 45 publications

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“…This is in keeping with observations in the setting of chronic viral infections (14,31). Conversely, a diverse TCR repertoire consisting of fewer highly expanded T-cell clones, which is known to be a hallmark of robust anti-viral T-cell immunity, might enhance broad tumor antigen control, thus making immune escape less likely (8)(9)(10). Consistent with this notion, it is known that subdominant T-cell clones can potentially target neo-antigens (6).…”

Section: Discussionsupporting

confidence: 61%

“…Here, a diverse repertoire of T cells has long been thought to be critical for effective host resistance to persistent infections (8)(9)(10)(11)(12). In longitudinal studies in patients with asymptomatic human immunodeficiency virus (HIV), a dynamic bi-directional adaptive interplay between viral epitope escape mutants and the T-cell clonal repertoire has been demonstrated (8).…”

Section: Introductionmentioning

confidence: 99%

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The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma

Keane

Gould

Jones

et al. 2017

Clinical Cancer Research

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Purpose: To investigate the relationship between the intratumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival.Experimental Design: We performed high-throughput unbiased TCRb sequencing on a population-based cohort of 92 patients with DLBCL treated with conventional (i.e., non-checkpoint blockade) frontline "R-CHOP" therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString. The primary endpoints were 4-year overall survival (OS) and progression-free survival (PFS).Results: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (P < 0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS rate of 60.0% [95% confidence interval (CI), 31.7%-79.6%], compared with 79.8% in patients with a low dominant clone (95% CI, 66.7%-88.5%; P ¼ 0.005). A highly dominant clone also predicted inferior 4-year PFS rate of 46.6% (95% CI, 22.5%-76.6%) versus 72.6% (95% CI, 58.8%-82.4%, P ¼ 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV þ DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell diversity was associated with significantly elevated PD-1, PD-L1, and PD-L2 immune checkpoint molecules. Conclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma

Keane

Gould

Jones

et al. 2017

Clinical Cancer Research

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“…[5-7] It is very likely that the clonal diversity of the CD4 + T-cell population and therefore breadth of pathogen recognition is also important. [8]…”

Section: Introductionmentioning

confidence: 99%

Supranormal thymic output up to 2 decades after HIV-1 infection

Aguilera-Sandoval

Yang

Jojić

et al. 2016

Aids

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Objectives AIDS is caused by CD4+ T-cell depletion. While combination antiretroviral therapy can restore blood T-cell numbers, the clonal diversity of the reconstituting cells, critical for immunocompetence, is not well defined. Methods We performed an extensive analysis of parameters of thymic function in HIV-1 infected (n=39) and control (n=28) subjects ranging from 13 to 23 years of age. CD4+ T-cells including naïve (CD27+ CD45RA+) and recent thymic emigrant (RTE) (CD31+/CD45RA+) cells, were quantified by flow cytometry. Deep sequencing was used to examine T cell receptor (TCR) sequence diversity in sorted RTE CD4+ T-cells. Results Infected subjects had reduced CD4+ T-cell levels with predominant depletion of the memory subset and preservation of naïve cells. RTE CD4+ T-cell levels were normal in most infected individuals, and enhanced thymopoiesis was indicated by higher proportions of CD4+ T-cells containing TCR recombination excision circles. Memory CD4+ T-cell depletion was highly associated with CD8+ T-cell activation in HIV-1-infected persons and plasma IL-7 levels were correlated with naïve CD4+ T-cells, suggesting activation-driven loss and compensatory enhancement of thymopoiesis. Deep sequencing of CD4+ T-cell receptor sequences in well-compensated infected persons demonstrated supranormal diversity, providing additional evidence of enhanced thymic output. Conclusions Despite up to two decades of infection, many individuals have remarkable thymic reserve to compensate for ongoing CD4+ T cell loss, although there is ongoing viral replication and immune activation despite cART. The longer-term sustainability of this physiology remains to be determined.

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“…It has been already shown that the diversity gets smaller when one had viral or bacterial infection, or when one became older. [23][24][25] Hence, we examined correlation between the TCR diversity in blood and the age of patients, but found no significant correlation between them (Fig. S1).…”

Section: Clonal T Cell Expansion In Tumors or Ascitesmentioning

confidence: 99%

Characterization of T cell repertoire of blood, tumor, and ascites in ovarian cancer patients using next generation sequencing

et al. 2015

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Tumor-infiltrating lymphocytes (TILs) play an important role in regulating the host immune response and are one of key factors in defining tumor microenvironment. Some studies have indicated that T cell infiltration in malignant ascites is associated with clinical outcome, but few studies have performed detailed characterization of T cell diversity or clonality in malignant effusions. We have applied a next generation sequencing method to characterize T cell repertoire of a set of primary cancers, ascites, and blood from 12 ovarian cancer patients and also analyzed the T cell subtype populations in malignant fluids from 3 ovarian cancer patients. We observed enrichment of certain T cells in tumors and ascites, but most of the enriched T cell receptor (TCR) sequences in tumors and ascites were not common. Moreover, we analyzed TCR sequences of T cell subtypes (CD4 C , CD8 C , and regulatory T cells) isolated from malignant effusions and also found clonal expansion of certain T cell populations, but the TCR sequences were almost mutually exclusive among the three subgroups. Although functional studies of clonally expanded T cell populations are definitely required, our approach offers a detailed characterization of T cell immune microenvironment in tumors and ascites that might differently affect antitumor immune response.

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Blood T-cell receptor diversity decreases during the course of HIV infection, but the potential for a diverse repertoire persists

Cited by 37 publications

References 45 publications

The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma

The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma

Supranormal thymic output up to 2 decades after HIV-1 infection

Characterization of T cell repertoire of blood, tumor, and ascites in ovarian cancer patients using next generation sequencing

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