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Thymic stromal lymphopoietin limits primary and recall CD8⁺ T-cell anti-viral responses.

ABSTRACT: Thymic stromal lymphopoietin (TSLP) is a cytokine that acts directly on CD4⁺ T cells and dendritic cells to promote progression of asthma, atopic dermatitis, and allergic inflammation. However, a direct role for TSLP in CD8⁺ T-cell primary responses remains controversial and its role in memory CD8⁺ T cell responses to secondary viral infection is unknown. Here, we investigate the role of TSLP in both primary and recall responses in mice using two different viral systems. Interestingly, TSLP limited the primary CD8⁺ T-cell response to influenza but did not affect T cell function nor significantly alter the number of memory CD8⁺ T cells generated after influenza infection. However, TSLP inhibited memory CD8⁺ T-cell responses to secondary viral infection with influenza or acute systemic LCMV infection. These data reveal a previously unappreciated role for TSLP on recall CD8⁺ T-cell responses in response to viral infection, findings with potential translational implications.

SUBMITTER: Ebina-Shibuya R

PROVIDER: S-EPMC7806261 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Thymic stromal lymphopoietin limits primary and recall CD8+ T-cell anti-viral responses.

Ebina-Shibuya Risa R West Erin E EE Spolski Rosanne R Li Peng P Oh Jangsuk J Kazemian Majid M Gromer Daniel D Swanson Phillip P Du Ning N McGavern Dorian B DB Leonard Warren J WJ

eLife 20210113

Thymic stromal lymphopoietin (TSLP) is a cytokine that acts directly on CD4+ T cells and dendritic cells to promote progression of asthma, atopic dermatitis, and allergic inflammation. However, a direct role for TSLP in CD8+ T-cell primary responses remains controversial and its role in memory CD8+ T cell responses to secondary viral infection is unknown. Here, we investigate the role of TSLP in both primary and recall responses in mice using two different viral ...[more]

PMID: 33439121

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Project description:Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.

Dataset Information

Thymic stromal lymphopoietin limits primary and recall CD8⁺ T-cell anti-viral responses.

Publications

Thymic stromal lymphopoietin limits primary and recall CD8<sup>+</sup> T-cell anti-viral responses.

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