Memory Phenotypes of HIV-Specific CD8+ T Cell Responses Are Independent of Functional Activity as Defined by Cytokine Output

Meika E I Richmond,Billy Nyanga,Sandra A Kiazyk,Charles Wachihi,T Blake Ball,Joshua Kimani,Lyle R Mckinnon,Makubo Kimani,Francis A Plummer

doi:10.4236/oji.2014.43012

Abstract

Objectives: The definition of CD8+ T cell attributes that mediate protective immunity in HIV dis-ease progression has not been clearly defined. Although our ability to characterize these cells continues to improve, the extent to which specific memory phenotypic categories of CD8+ T cells reliably represent their functional attributes remains controversial. Methods: We simultaneously assessed surface phenotype and functionality of HIV-specific CD8+ T cells by multiparametric flow cytometry, measuring five CD8+ T cell functions (CD107a, IFNγ, MIP-1β, TNFα and IL2) and phenotypic markers CCR7, CD45RA, and CD27, in parallel in 24 HIV-infected individuals. Results: Virus-specific responses were contained within all eight phenotypic categories defined using CCR7, CD45RA, and CD27. Phenotypic profiles of HIV-specific cells differed from CEF-specific cells, with HIV-specific cells having higher levels of CD45RA (p = 0.008). Interestingly a large portion of CEF and HIV-specific cells were found within previously undefined phenotypes CCR7+CD27－CD45RA+ (14.6% and 17.2%, respectively) and CCR7+CD27－CD45RA－(14.8% and 15.8%, respectively). In addition, up to 10% - 20% of responding cells were phenotypically “naive”. Additionally, memory phenotypes of cells exhibiting monofunctional and polyfunctional responses frequently differed, and failed to associate with a consistent phenotype representing functionally active cells. Conclusion: These data suggest that particularly after antigen stimulation, that surface phenotypes defined by CCR7, CD27 and CD45RA expression on antigen-specific CD8+ T cells, reflect a wide range of immunological functions, and that no single phenotype defined by memory marker expression can reliably be used to identify functional capacity.

Highlights

Virus-specific CD8+ T cells are phenotypically and functionally heterogeneous, and a better understanding of specific subsets critical for protective immunity in human immunodeficiency virus (HIV) infection is needed for rationale vaccine design and immune monitoring
The most common approach measures the expression of the homing marker CCR7 and the T cell differentiation marker CD45RA to define cells as central memory (TCM), effector memory (TEM), and naive effector [1]-[3]
Antiretroviral therapy (ART) naive subjects with CD4+ counts above 400 cells/μl for over 6 years were classified as long-term non-progressors (LTNP)

Summary

Introduction

Virus-specific CD8+ T cells are phenotypically and functionally heterogeneous, and a better understanding of specific subsets critical for protective immunity in human immunodeficiency virus (HIV) infection is needed for rationale vaccine design and immune monitoring. With the widespread use of polychromatic flowcytometry, an increasing number of functional parameters of T cell responses can be assessed simultaneously. These responses comprise a number of functional parameters including cytokine and chemokine expression and cytotoxic markers. An often complementary approach has been the use of surrogate surface phenotypic markers to help define the functional capacity of antiviral T cells. The most common approach measures the expression of the homing marker CCR7 and the T cell differentiation marker CD45RA to define cells as central memory (TCM), effector memory (TEM), and naive effector [1]-[3]. CD8+ T cells expressing CCR7+CD27+CD45RA+ are considered to be functionally naive, while CCR7−CD27−CD45RA+/−

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Conclusion