Abstract
Recovery of the T lymphocyte compartment within a lymphopenic host by lymphopenia-induced proliferation (LIP) is regulated by inter- and intraclonal competition for limited resources, including homeostatic cytokines and peptide:MHC (pMHC) complexes with which the TCR can interact at least weakly to yield a tonic signal. Importantly, the process of LIP can synergize with other factors that promote T cell activation to drive inflammatory disease. While reconstitution of the lymphoid compartment of immune deficient Rag−/− mice by transfer of wild-type hematopoietic stem cells (HSC) does not generally result in an overt disease phenotype, transfer of HSC deficient in expression of the co-inhibitory molecule PD-1 results in severe systemic autoimmunity driven by newly generated T cells that emerge from the thymus into the periphery and undergo LIP. Importantly, autoimmunity does not appear to depend on a response to exogenous (i.e., gut flora-derived) antigens. PD-1 is well known to be upregulated during T cell activation in response to cognate antigens, but it is unclear whether PD-1 has a role in controlling LIP of T cells in the absence of cognate antigen, i.e., in response to tonic pMHC. We examined whether PD-1 controls LIP of newly generated T cells by controlling the response to tonic pMHC or the homeostatic cytokine IL-7. We found that PD-1-deficient T cells have a proliferative advantage over WT T cells during LIP and this effect is MHC-II dependent and independent of IL-7Rα signaling. Furthermore, our data suggest that signals through IL-7Rα can be dispensable for LIP and may instead be of increased importance for T cell survival in conditions of high competition for limited pMHC (e.g., post-LIP, in a lymphoreplete host). We hypothesize that autoimmunity post-PD-1−/− HSC transplant is the result of an overzealous T cell response to normally tonic self-pMHC precipitated by the synergy of LIP and PD-1 deficiency. Furthermore, potentiation of TCR signals in response to normally tonic self-pMHC may contribute to the success of PD-1 blockade in cancer immunotherapy.
Highlights
The number of cells in and diversity of the peripheral T lymphocyte pool is controlled by intraand interclonal competition for resources, which together define T cell “space” [1]
We have previously demonstrated that transfer of a mixture of Treg-depleted polyclonal WT and PD-1−/− CD4+ T cells purified from the thymocyte or splenocyte population into lymphopenic Rag−/− hosts resulted in predominance of the PD-1−/− population in the periphery during lymphopeniainduced proliferation (LIP) [33]
The potential for LIP in a host depends on the resources available for T cells relative to the level of competition for those resources [1]
Summary
The number of cells in and diversity of the peripheral T lymphocyte pool is controlled by intraand interclonal competition for resources, which together define T cell “space” [1]. Such resources include homeostatic cytokines like IL-7 and IL-15, and peptide:MHC (pMHC) complexes; often self-pMHC, with which the TCR can interact and receive at least a weak “tonic” signal to promote. Positive or negative regulation of the strength of the TCR signal a lymphocyte receives in response to a given pMHC, for example by blocking/reducing co-inhibition [15,16,17,18,19] or co-stimulation [9], respectively, can modulate LIP potential. A neonatal host might be viewed to have a low LIP potential due to small anatomic size (low absolute quantities of resources) as well as the recently described presence of an innate lymphoid cell population that may act as a sink for IL-7 [20]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
