Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype

Abstract

We studied CD8 T cell responses against HIV-1, cytomegalovirus, Epstein-Barr virus, and influenza in 128 subjects and demonstrate that polyfunctional CD8 T cell responses, also including IL-2 production and Ag-specific proliferation, are predominantly driven by virus epitopes restricted by HLA-B alleles. Interestingly, these protective CD8 T cells are equipped with low-avidity T cell receptors (TCRs) for the cognate virus epitope. Conversely, HLA-Arestricted epitopes are mostly associated with ''only effector'' IFN-␥-secreting, with cytotoxicity, and with the lack of IL-2 production and Ag-specific proliferation. These CD8 T cells are equipped with high-avidity TCR and express higher levels of the T cell exhaustion marker PD-1. Thus, the functional profile of the CD8 T cell response is strongly influenced by the extent to which there is stimulation of polyfunctional (predominantly restricted by HLA-B) versus only effector (restricted by HLA-A) T cell responses. These results provide the rationale for the observed protective role of HLA-B in HIV-1-infection and new insights into the relationship between TCR avidity, PD-1 expression, and the functional profile of CD8 T cells.

Influenza Epitope-Specific CD8+ T Cell Avidity, but Not Cytokine Polyfunctionality, Can Be Determined by TCRβ Clonotype

“…This was particularly intriguing for the D b PA 224 -specific population, where we saw clear partitioning of clonotypes in the highavidity subset, and suggests that polyfunctionality (at least for this epitope) is not a selective characteristic of the high-avidity population. This is supported by one study (15) in which polyfunctionality correlated more closely with the HLA restriction element and was inversely correlated with avidity, but contrasts with a number of other studies (including our own) that have indicated a link between the strength of the TCR-pMHCI interaction and the propensity to produce multiple cytokines (6,7,13,14,19). Critically, however, the nexus between avidity and polyfunctionality in the majority of these studies was correlative, leaving open the possibility that these two effects segregate independently.…”

“…Although there have been several reports linking the functional profiles of T cell populations and their avidity or sensitivity to Ag (6,13,14), these analyses have been largely correlative. Furthermore, other evidence suggests that polyfunctional HIV-specific T cells partition preferentially with the set showing lower TCR avidity (15). Thus, the key determinants of polyfunctionality in virus-specific CD8 + T cells, particularly the role of T cell avidity, remain unclear.…”

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

“…All medium and supplements were purchased from Invitrogen (Carlsbad, CA). [18][19][20][21][22][23][24][25][26][27] were from ProImmune (Oxford, U.K.). For intracellular cytokine staining (ICS) multicolor FACS staining, TCR-transduced PBMCs were incubated overnight with indicated stimuli.…”

“…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). Although high-avidity CTLs are superior for viral and tumor clearance, they also have a greater sensitivity to Ag-induced cell death.…”

“…Although high-avidity CTLs are superior for viral and tumor clearance, they also have a greater sensitivity to Ag-induced cell death. 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.…”