Abstract
In lymphopenic mice, T cells become activated and undergo lymphopenia-induced proliferation (LIP). However, not all T cells are equally sensitive to lymphopenia. Several lymphopenia-insensitive T cell clones were described and their non-responsiveness was mainly attributed to clone-specific properties. Here, we provide evidence for an additional, host-dependent mechanism restraining LIP of lymphopenia-insensitive CD4+ T cells. We show that such cells undergo LIP in lymphopenic mice lacking IFN-γ receptor (IFN-γR) expression, a process, which is promoted by the autocrine action of T cell-derived IFN-γ. Additionally, LIP of lymphopenia-insensitive CD4+ T cells requires an intact microflora and is accompanied by the massive accumulation of IL-6 and dendritic cells (DCs). Consistent with these results, IL-6 neutralization and the DC-specific restoration of IFN-γR expression are both sufficient to restrict LIP. Hence, the insensitivity of CD4+ T cells to lymphopenia relies on cell-intrinsic properties and a complex interplay between the commensal microflora, IL-6, IFN-γR+ DCs, and T cell-derived IFN-γ.
Highlights
In lymphocyte-competent hosts, T cells continuously utilize homeostatic factors such as Interleukin-7 (IL-7) and self-peptide-MHC complexes and thereby limit their availability [1]
We show that the commensal microflora is crucial for OT-II lymphopenia-induced proliferation (LIP) in RagγRko mice, which is accompanied by the massive expansion of dendritic cells (DCs)
We have shown that host IFN-γ receptor (IFN-γR) signaling restricts LIP of CD8+ T cells [22]
Summary
In lymphocyte-competent hosts, T cells continuously utilize homeostatic factors such as Interleukin-7 (IL-7) and self-peptide-MHC complexes and thereby limit their availability [1]. The adoptive transfer of polyclonal naive CD4+ T cells into lymphopenic mice leads to their activation and subsequent lymphopenia-induced proliferation (LIP) [5, 6]. TCR signal strength is a major factor that regulates the sensitivity of a T cell to lymphopenia [15, 16]. We show that the commensal microflora is crucial for OT-II LIP in RagγRko mice, which is accompanied by the massive expansion of dendritic cells (DCs). We provide evidence that the suppression of CD4+ T cell activation in response to lymphopenia is determined by a combination of both, clone-specific properties and environmental factors such as the commensal microflora, IL-6 and IFN-γR expression by DCs
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.
