A role for cell‐autocrine interleukin‐2 in regulatory T‐cell homeostasis

Abstract

SummaryActivated T‐cells make both interleukin‐2 (IL2) and its high‐affinity receptor component CD25. Regulatory CD4 T‐cells (Treg cells) do not make IL2, and the IL2‐CD25 circuit is considered a paracrine circuit crucial in their generation and maintenance. Yet, all T‐cells are capable of making IL2 at some stage during differentiation, making a cell‐intrinsic autocrine circuit additionally possible. When we re‐visited experiments with mixed bone marrow chimeras using a wide range of ratios of wild‐type (WT) and IL2−/− genotype progenitors, we found that, as expected, thymic Treg cells were almost equivalent between WT and IL2−/− genotypes at ratios with WT prominence. However, at WT‐limiting ratios, the IL2−/− genotype showed lower thymic Treg frequencies, indicating a role for cell‐intrinsic autocrine IL2 in thymic Treg generation under IL2‐limiting conditions. Further, peripheral IL2−/− naive CD4 T‐cells showed poor conversion to inducible Tregs (pTregs) both in vivo and in vitro, again indicating a significant role for cell‐intrinsic autocrine IL2 in their generation. Peripherally, the IL2−/− genotype was less prominent at all WT:IL2−/− ratios among both thymic Tregs (tTregs) and pTregs, adoptively transferred IL2−/− Tregs showed poorer survival than WT Tregs did, and RNA‐seq analysis of WT and IL2−/− Tregs showed interesting differences in the T‐cell receptor and transforming growth factor‐beta‐bone morphogenetic protein‐JNK pathways between them, suggesting a non‐titrating role for cell‐intrinsic autocrine IL2 in Treg programming. These data indicate that cell‐intrinsic autocrine IL2 plays significant roles in Treg generation and maintenance.

Dysregulated B cell differentiation towards antibody-secreting cells in neuromyelitis optica spectrum disorder

“…Furthermore, their expansion may result in an increase of SMB cells and plasmablasts and the continuous production of autoantibodies in NMOSD patients. Autocrine IL-2 was reported to be involved in the survival and differentiation of T cells [32][33][34]. However, to the best of our knowledge, there is no evidence for the production of IL-2 from B cells.…”

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

“…The phenotypic similarity between IL-2-producing and nonproducing Foxp3 + cells and the equivalent production in cells with long-term stable Foxp3 expression are most consistent with the incomplete silencing of the Il2 locus by Tregs, with a partially preserved IL-2 production and secretion capacity. This incomplete silencing explains recent findings that Il2 −/− Tregs have poorer survival upon lymphopenic transfer (Chawla et al, 2020).…”

Immunological impact of tetrahydrobiopterin on the central nervous system in a murine model of rabies virus infection

“…Interestingly, the experimental group (p=0.014), showed less IL-2 depletion, which is extremely important mainly for the maturation of T and B lymphocytes, being responsible for the innate and adaptive immune response, respectively. The total non-depletion of IL2 is necessary for activities within the micro environment of the CNS, as it will assist in the maturation of white cells for the immediate innate response and controlling the viral dispersion within the CNS 28 - 33 .…”