Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity

Abstract

CD8 ؉ T cells are major players in the immune response against HIV. However, recent failures in the development of T cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell-mediated efficacy. CD8 ؉ T cells from HIV-1-infected patients with slow disease progression exhibit potent polyfunctionality and HIVsuppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIVspecific CD8 ؉ T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8 ؉ T cells from infected donors. We report that attributes of CD8 ؉ T-cell effi- IntroductionCD8 ϩ T cells are essential for effective immunity against HIV-1, and the induction of such responses using vaccines has become a major objective in the strategy to halt the pandemic. 1 However, the recent outcome of the Merck STEP study, the most ambitious trial of an anti-HIV T cell-based vaccine conducted to date, has been a major disappointment. 2 Despite its immunogenicity, the vaccine failed both to prevent infection of vaccinated volunteers at high risk of acquiring HIV and to reduce viral load set points in infected vaccinees. This failure has roused the scientific community to step back and reconsider its basic knowledge of T cell-mediated efficacy. 3,4 Indeed, consensual opinion is that our general understanding of T-cell efficacy in HIV-1 infection is actually still limited, which represents a clear obstacle to the design of successful vaccines.Over recent years, qualitative attributes of CD8 ϩ T cells have increasingly become the focus of attempts to identify reliable correlates of immune protection against HIV. Among these, polyfunctionality 5 and HIV-suppressive activity 6 have been associated with spontaneous control of HIV infection and slower disease progression rates in infected patients. Of note, polyfunctionality is currently seen as the best correlate of T-cell efficacy measurable directly ex vivo. 7 Polyfunctional CD8 ϩ T cells are those that exhibit multiple effector functions (ie, degranulation and production of antiviral factors) simultaneously upon antigen encounter; this can be assessed after stimulation with cognate peptides by multiparametric flow cytometry (eg, mobilization of CD107 and intracellular production of interferon [IFN]-␥, tumor necrosis factor [TNF]-␣, interleukin-2 [IL-2], and macrophage-inflammatory protein [MIP]-1␤). 5 HIV-suppressive activity reflects the capacity of HIV-specific CD8 ϩ T cells to eliminate HIV-infected targets via classical class I major histocompatibility complex (MHC)-restricted cytotoxic lysis. 6,8 It can be assessed using primary CD4 ϩ T cells infected in vitro with HIV in the presence of...

In vivoModulation of Avidity in Highly Sensitive CD8+Effector T Cells Following Viral Infection

“…In the case of viral infections, the increased efficacy of high avidity CTL results, at least in part, from their ability to recognize virus-infected cells very early after infection (22). The crucial involvement of high avidity CTL in the clearance of viruses and tumors has been confirmed in a number of studies (5,6,28,34,43,55,61,63). That said, there may be circumstances wherein lower avidity cells play a critical role.…”

TCR-Redirected Human T Cells Inhibit Hepatitis C Virus Replication: Hepatotoxic Potential Is Linked to Antigen Specificity and Functional Avidity

“…Selection of high-avidity CD8 T cells correlates with control of viral infections and polyfunctional profiles as well as potent virussuppressive activity including HCV (16,17). Notwithstanding the intrinsic superior antiviral activity of higher avidity TCR CD8 T cells, low-avidity TCR polyfunctional CD8 T cells have been suggested to be more fit in providing disease control during chronic virus infection (18) and have been reported to reject tumors and can have less problems regarding immune pathology (19).…”

“…As with chronic infections, such as HIV and HCV, as well as in cancer, the host may lose (by clonal exhaustion or other apoptotic mechanisms) the effector cells that are most critical for viral or tumor clearance (18). In the case of HCV, the high-avidity T cells have been suggested to control HCV infection (16,17); however, what remains unclear is whether low avidity T cells may contribute to antiviral mechanisms against the HCV-infected cells.…”

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

“…It was proposed that a correlate of protection in HIV infection is the presence of T cells of high functional avidity and, further, that these high-avidity T cells also were of increased polyfunctionality (7,8). Interestingly, although we found that low vaccine Ag doses induced CD4 T cells of higher functional avidity and greater polyfunctionality (Fig.…”

“…Increasing the functional avidity of T cells in vivo through immunization is a promising strategy to increase vaccine efficacy against infectious diseases and tumors (3)(4)(5)(6)(7)(8)(9).…”