Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor

Abstract

HIV’s phenomenal capacity to vary its HLA-I-restricted peptide antigens allows it to escape from host cytotoxic T-lymphocytes (CTLs). Nevertheless, therapeutics able to target HLA-I-associated antigens, with specificity for the spectrum of preferred CTL escape mutants, could prove effective. Here we use phage display to isolate and enhance a T-cell receptor (TCR) originating from a patient CTL line and specific for the immunodominant HLA-A*02-restricted, HIVgag-specific peptide SLYNTVATL (SL9). High affinity (KD <400pM) TCRs were produced that bound with a half-life in excess of three hours, retained specificity, targeted HIV-infected cells and recognized all common escape variants of this epitope. CD8 T-cells transduced with supraphysiologic TCR produced a greater range of soluble factors and more IL2, than those transduced with natural SL9-specific TCR, and effectively controlled wildtype and mutant strains of HIV at effector-to-target ratios that could be achieved by T-cell therapy.

T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy

“…In summary, both in vitro and the in vivo antitumor activities of gp209-specific TCRs reach a maximum at a defined avidity and affinity threshold (K D , ∼10μM). Previous studies of the relationship between TCR affinity and T-cell function have led to controversial conclusions (12,17,(22)(23)(24)(25). Here, we demonstrated a plateaued correlation in a self-antigen system in both in vivo and in vitro settings, which has far broader implications for clinical applications.…”

“…Subsequently, efforts have been taken to generate modified high-affinity TCRs for clinical studies (19)(20)(21). However, this correlation remains controversial: high-affinity TCRs have been shown to lead to stronger (22), plateaued (12,17), or even attenuated (23)(24)(25) T-cell responses. Underlying reasons for this controversy could be that antigens previously analyzed were derived from models that induce unusually strong T-cell responses that do not reflect immune responses against true self-antigens, which tend to be less robust.…”

Germ Line-governed Recognition of a Cancer Epitope by an Immunodominant Human T-cell Receptor

“…Furthermore, there are no examples to date of human TCR⅐pMHC class I structures in which the bound peptide is a decamer; this represents a substantial deficiency in our current knowledge, given the preponderance with which decamer peptides are processed, presented, and recognized. The low number of TCR⅐pMHC complex structures solved to date reflects technical difficulties inherent in the production of soluble TCR and pMHC molecules that retain stability and challenges related to the crystallization of complexes with relatively low binding affinities (K D ϭ 0.1-500 M) (21,22). In general, TCRs specific for tumor-derived epitopes bind in the weaker range of TCR/ pMHC affinities (21).…”

Relevance of the T cell Receptor-Ligand Avidity for Immunity to Infection

“…For example, Appay et al [9] identify that CD8 + -specific responses are crucial in the immune control of HIV, and that high avidity T cells result in superior control of viral replication by exerting a greater selective pressure on variable viruses, which as a result exhibit reduced replicative fitness, elegantly demonstrated in the work of VarelaRohena et al [34] Similarly, Sud et al [35] identify the importance of cytotoxic T cells in controlling infections of M. tuberculosis, in cooperation with other members of the adaptive immune system. Aside from the application of the k off -rate assay to adoptive cell therapies, the assay has the potential to be of great advantage in diagnostic settings.…”