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NK1.1+ CD8+ T cells escape TGF-? control and contribute to early microbial pathogen response.

ABSTRACT: Following microbial pathogen invasion, one of the main challenges for the host is to rapidly control pathogen spreading to avoid vital tissue damage. Here we report that an effector CD8(+) T-cell population that expresses the marker NK1.1 undergoes delayed contraction and sustains early anti-microbial protection. NK1.1(+) CD8(+) T cells are derived from CD8(+) T cells during priming, and their differentiation is inhibited by transforming growth factor-? signalling. After their own contraction phase, they form a distinct pool of KLRG1 CD127 double-positive memory T cells and rapidly produce both interferon-? and granzyme B, providing significant pathogen protection in an antigen-independent manner within only a few hours. Thus, by prolonging the CD8(+) T-cell response at the effector stage and by expressing exacerbated innate-like features at the memory stage, NK1.1(+) cells represent a distinct subset of CD8(+) T cell that contributes to the early control of microbial pathogen re-infections.

SUBMITTER: Ruiz AL

PROVIDER: S-EPMC4836950 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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NK1.1+ CD8+ T cells escape TGF-β control and contribute to early microbial pathogen response.

Ruiz Anne L AL Soudja Saidi M'Homa SM Deceneux Cyril C Lauvau Grégoire G Marie Julien C JC

Nature communications 20141006

Following microbial pathogen invasion, one of the main challenges for the host is to rapidly control pathogen spreading to avoid vital tissue damage. Here we report that an effector CD8(+) T-cell population that expresses the marker NK1.1 undergoes delayed contraction and sustains early anti-microbial protection. NK1.1(+) CD8(+) T cells are derived from CD8(+) T cells during priming, and their differentiation is inhibited by transforming growth factor-β signalling. After their own contraction ph ...[more]

PMID: 25284210

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Project description:During early human immunodeficiency virus (HIV) infection multiple CD8+ T cell responses are elicited almost simultaneously. These responses exert strong selective pressures on different parts of HIV's genome, and select for mutations that escape recognition and are thus beneficial to the virus. Some studies reveal that the later these escape mutations emerge, the more slowly they go to fixation. This pattern of escape rate decrease(ERD) can arise by distinct mechanisms. In particular, in large populations with high beneficial mutation rates interference among different escape strains--an effect that can emerge in evolution with asexual reproduction and results in delayed fixation times of beneficial mutations compared to sexual reproduction--could significantly impact the escape rates of mutations. In this paper, we investigated how interference between these concurrent escape mutations affects their escape rates in systems with multiple epitopes, and whether it could be a source of the ERD pattern. To address these issues, we developed a multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference. We also derived an interference-free null model assuming initial neutral evolution before immune response elicitation. We found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern. We also found that the number of loci, as well as recombination rates substantially affect ERD. These effects can be explained by the underexponential decline of escape rates over time. Lastly, we found that the observed ERD pattern in HIV infected individuals is consistent with both independent, interference-free mutations as well as interference effects. Our results confirm that interference effects should be considered when analyzing HIV escape mutations. The challenge in estimating escape rates and mutation-associated selective coefficients posed by interference effects cannot simply be overcome by improved sampling frequencies or sizes. This problem is a consequence of the fundamental shortcomings of current estimation techniques under interference regimes. Hence, accounting for the stochastic nature of competition between mutations demands novel estimation methodologies based on the analysis of HIV strains, rather than mutation frequencies.

Dataset Information

NK1.1+ CD8+ T cells escape TGF-? control and contribute to early microbial pathogen response.

Publications

NK1.1+ CD8+ T cells escape TGF-β control and contribute to early microbial pathogen response.

Similar Datasets

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