TRAILshort Protects against CD4 T Cell Death during Acute HIV Infection

Abstract

CD4 T cells from HIV-1 infected patients die at excessive rates compared to those from uninfected patients, causing immunodeficiency. We previously identified a dominant negative ligand that antagonizes the TRAIL-dependent pathway of cell death, which we called TRAILshort. Because the TRAIL pathway has been implicated in CD4 T cell death occurring during HIV-1 infection, we used short hairpin RNA knockdown, CRISPR deletion, or Abs specific for TRAILshort to determine the effect of inhibiting TRAILshort on the outcome of experimental acute HIV infection in vitro. Strikingly, all three approaches to TRAILshort deletion/inhibition enhanced HIV-induced death of both infected and uninfected human CD4 T cells. Thus, TRAILshort impacts T cell dynamics during HIV infection, and inhibiting TRAILshort causes more HIV-infected and uninfected bystander cells to die. TRAILshort is, therefore, a host-derived, host-adaptive mechanism to limit the effects of TRAIL-induced cell death. Further studies on the effects of TRAILshort in other disease states are warranted.

Identification of pathogenic TRAIL-expressing innate immune cells during HIV-1 infection in humanized mice by scRNA-seq

“…It has been reported that plasma levels of soluble TRAIL are increased in patients infected with HIV (39). Furthermore, an alternative spliced form of TRAIL named TRAIL-short can be induced by HIV-1 infection and is reported to protect against CD4 + T cell death during acute HIV-1 infection (46,47). In the present study, we did not observe any significant induction of soluble TRAIL in the plasma of NRG-hu HSC mice at 3-5 weeks after HIV-1 infection.…”

Human Cancers Express TRAILshort, a Dominant Negative TRAIL Splice Variant, Which Impairs Immune Effector Cell Killing of Tumor Cells

“…Interestingly, TRAILshort is found in extracellular vesicles, which are elaborated from TRAILshort expressing cells, and these vesicles can confer TRAIL resistance upon otherwise TRAILsensitive bystander, neighboring cells (12). Finally, we have observed that interfering with TRAILshort function using inhibitory antibodies alters T-cell dynamics following acute HIV infection in vitro (13,14).…”

“…The following cell lines were also used: Jurkat (ATCC), HBL-1 (Ansell Lab, Mayo Clinic), OCI-LY3 (DSMZ), JeKo-1 (ATCC), RPMI8226 (ATCC), BCWM.1 (Ansell Lab, Mayo Clinic), Ovcar8 (NCI-DTP), Hovtax2 (John Copland Lab, Mayo Clinic), Cov362 (ECACC), Caov3 (ATCC), Ovcar5 (NCI-DTP) PEO1 (ECACC) TYK-nu (JCRB), L3.6 (Daniel Billadeau Lab, Mayo Clinic), BxPC-3 (ATCC;), HepG2 (ATCC), HLE (JCRB), EM-Meso (Tobias Peikert Lab, Mayo Clinic); MDA-MB231 (ATCC), and Sk-Mel-28 (ATCC). TRAIL knockout Jurkat T cells were described previously (13).…”

“…We assessed primary human cancer tissues for TRAILshort protein by IHC, using a mouse monoclonal anti-TRAILshort antibody which we have validated previously (11), and by TRAILshort message specific ISH. The anti-TRAILshort antibody was developed and validated to recognize the unique C-terminal 11 amino acids encoded by TRAILshort (13). The TRAILshort ISH probes target the novel splice junction not present in full-length TRAIL message.…”

The long road to TRAIL therapy: a TRAILshort detour

“…This protein was seen to occupy the TRAIL receptors DR4 and DR5 without inducing cell cytotoxicity and prevent TRAIL-induced cell cytotoxicity. Further investigation revealed that antagonizing this protein with a monoclonal antibody resulted in the re-sensitization of TRAIL-resistant cells to TRAIL-mediated apoptosis [ 20 ].…”