P08. HIV-induced modifications of TIGIT expression impair CD8 T cell polyfunctionality

Lydia Scharf1, Johanna Tauriainen1, Michael R Betts2, Marcus Buggert2,3, Annika C Karlsson1
Affiliates: 1Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 2Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America; 3Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;

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CD8 T cells are of major importance for diminishing HIV replication after acute infection. However, during chronic HIV infection the CD8 T cell response undergoes severe exhaustion. This process manifests in the accumulation of inhibitory receptors and loss of co-stimulators, imbalance of specific transcription factors and impairment of several functional features. The dysregulations in expression can be seen for most receptors involved in T cell function, such as the co-inhibitor T cell immunoglobulin and ITIM domain (TIGIT) and the complementary co-stimulator CD226. TIGIT is expressed on NK and CD8 T cells and impairs cytotoxity of NK cells via multiple mechanisms: signaling via its immunoreceptor tyrosine-based inhibitory motif (ITIM) upon ligand binding, inhibiting CD226 dimerization, downregulation of the co-stimulator and outcompeting CD226 in binding to the shared ligand poliovirus receptor (PVR).

Peripheral blood mononuclear cells (PBMCs) and lymph node mononuclear cells (LNMCs) were stained with antibodies and analyzed using multicolor flow cytometry. We analyzed TIGIT expression on CD8 T cells from distinct patient cohorts as well as longitudinally after initiation of antiretroviral treatment (ART). Antigen-specific CD8 T cells were identified by peptide stimulation and cytokine detection.

We detected elevated frequencies of TIGIT expression among CD8 T cells in both chronically infected patient groups, long-term treated and treatment-naïve. Furthermore, the TIGIT-positive cells continue to accumulate despite ART. Comparing HIV- to CMV-specific CD8 T cells, we found an elevated frequency of TIGIT-positive cells and less CD226-posisitve cells among the population recognizing HIV. In addition, we detected upregulation of PVR on CD4 T cells within blood and lymph node samples from HIV-infected patients. Within the lymph nodes, this upregulation was especially pronounced on follicular T helper cells (Tfh).

Our results show increased TIGIT and PVR expression as well as a decrease in CD226 during chronic HIV. These modifications of the TIGIT/CD226/PVR axis towards CD8 T cell inhibition are likely to contribute to the CD8 T cell exhaustion and HIV persistence seen in HIV patients. The characteristics of CD8 T cell exhaustion have important implications for future HIV research, especially when intending a “shock and kill” approach.