DISCUSSION
During a typical CD8+ T cell immune response, a range
of clonotypes are recruited, each with their own distinct affinity for
the target epitope. In this study we identified an HCV-specific
clonotype from an individual with acutely resolved infection that was
monoclonal expanded and exhibited a strong affinity for the HLA-B*07:02GPR epitope, with a dissociation rate significantly smaller than
the ones of previously reported TCRs13,14.
Intriguingly, a polyclonal repertoire from a second individual that also
generated a response against the same epitope also exhibited similar
dissociation rates, suggesting that affinity alone may not be a
sufficient factor regulating whether monoclonal or polyclonal
populations arise.
Our findings provide evidence that high-affinity TCRs may be more common
than previously observed, or particular epitopes may bias the
recruitment of higher affinity receptors. Previous studies of TCR
dissociations using the same assay have reported half-lives typically of
up to 200 seconds 13,14,23, which was exceeded by all
GPR-specific clonotypes in this study.
The affinity between a TCR and its target pMHC is particularly
meaningful for dictating the activation potency of
CD8+ T cell clones24 which may have
contributed to the accelerated differentiation and expansion of the
monoclonal GPR-specific clonotype at the expense of recruitment of
additional clonotypes. It is plausible that the range of affinities
measured from our colony expansions may have been biased to favour
subsets such as central memory T cells which have greater capacity for
clonal expansion in vitro by cytokine stimulation25 or high affinity clonotypes which are more
responsive to memory recall responses 26,27.
The role of affinity in determining T cell fate remains unclear, with
contrasting reports on the role of high affinity in driving memory T
cell fate28-30. High-affinity clones were found
dominating during the acute phase of infection, while under chronic
conditions, low-affinity repertoires may be favoured through mechanisms
such as mutational escape epitopes upon viral evolution or re-infection18. Our new study is consistent with a model that
high-affinity memory cells can be detected in the acute phase of viral
infection, and these are phenotypically and transcriptionally distinct
from effector cells that contribute to IFN-𝛾
production19. In this study we studied high-risk
behaviour individuals who inject drugs, thus it is likely that
continuous exposure to HCV may contribute to the formation of memory
populations, and therefore to future protective immunity31,32. Nevertheless, more studies are needed to
dissect the role of affinity in determining the fate of a cytotoxic T
cell response33 and whether the affinity profile of
memory populations continue to be shaped by future antigen encounter.
Our findings will benefit the growing field of personalized
immunotherapies involving the rational TCR design. Notably, rational
engineering of the monoclonal receptor offers the possibility to further
enhance its affinity, for example to synthesize specific high-affinity
TCRs against neoantigen targets34.