The TRAIL of Helpless CD8⁺T Cells in HIV Infection

Abstract

Our understanding of how CD4 ϩ T cells can regulate CD8 ϩ T cell responses in HIV infection is still incomplete. Recent evidence obtained in mice suggests that CD4 ϩ T cell help is required for efficient CD8 ϩ T cellmediated immunity in chronic infection: CD8 ϩ T cells primed in the absence of such help release the TNF-related apoptosis-inducing ligand TRAIL and undergo apoptosis. Using a novel ELISPOT assay, in the present study we show that CD8 ϩ T cells are also a source of the antigen-specific TRAIL response in HIV-infected patients with CD4 ϩ T cell counts below 200. In patients with CD4 ϩ T cell counts above 200 TRAIL was not detectable. Accordingly, antigens to which patients have likely been exposed when CD4 ϩ T cell levels were high (e.g., influenza, CMV, and EBV) did not induce TRAIL. Within the HIV-positive donor population with low CD4 ϩ T cell counts a dissociation of the interferon-␥ (IFN-␥) and TRAIL response to different HIV peptide epitopes was detectable suggesting impaired immunity to antigens that triggered TRAIL in the absence of IFN-␥. Our findings emphasize that "helpless" CD8 ϩ T cells, i.e., cells that have been primed in the absence of CD4 ϩ T cell help, may play a crucial role in HIV infection. A "helpless" phenotype may impair CD8 ϩ T cell control of HIV and other infections and possibly contribute to the depletion of CD4 ϩ T cells via apoptosis. Immunizations and infections in this "helpless" state might result in ineffective CD8 ϩ T cell responses. 1175

Signaling through the P38 and ERK pathways: a common link between HIV replication and the immune response

“…These markers and cytokines are associated with exhaustion and/ or apoptosis. There are other markers and cytokines linked to P38 activation, which are also shown to be elevated in HIV-1 infection including TGF-b1 [49] and TRAIL [50]. Additional analysis of these immunological markers in HIV infection may further emphasize the critical role of P38 signaling in HIV infection.…”

“…They concluded that sustained ERK activation was required to produce IL-2 through T-cell receptor activation. TNF-a Inflammation [42] HIV* TGF-bl, TRAIL Exhaustion, Apoptosis [49,50] * Biomarkers that are upregulated in HIV-1 infection and play a role in the P38 pathway, but without a reported connection between HIV and P38…”

Therapeutic applications of TRAIL receptor agonists in cancer and beyond

“…Specifically, CD8 + T cells activated without CD4 + T cell help express TRAIL and undergo AICD upon secondary Ag stimulation (Janssen et al, 2005; Wolkers et al, 2011; Feau et al, 2012; Wolkers et al, 2012). Immune unresponsiveness associated with the generation of such TRAIL-expressing ‘helpless’ CD8 T cells has been reported in a number of experimental models and clinical settings (Hamilton et al, 2006; Griffith et al, 2007; Kuerten et al, 2008; Gurung et al, 2010; Unsinger et al, 2010; Griffith et al, 2011; Gurung et al, 2011), but this concept has proven to be more tenuous in some models of infection (see below) (Badovinac et al, 2006; Sacks & Bevan, 2008). However, apoptosis does not always result in tolerance, as it seems to be the case of lymphocyte apoptosis.…”

Coinfection With HIV-1 and HCV—A One-Two Punch

“…204 It will be interesting to determine whether CD8 + T cells primarily express TRAIL within the intracellular inflammatory milieu of an HCV-infected liver and whether TRAIL blockade can restore T-cell function and reverse hepatotoxicity. 205 …”