A role for cell‐autocrine interleukin‐2 in regulatory T‐cell homeostasis. Issue 3 (14th April 2020) - Chawla, Amanpreet Singh
Summary: Activated 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. Abstract : While intercellular interactions are commonly visualized as paracrine, in that they are mediated by either receptor‐counter‐receptor engagement or by aqueous‐phase molecules secreted by one cell binding to receptors on another cell, individual cells can also sense their own signals in a cell‐autocrine fashion, and examples of biological circuits formed from the resultant modulation of self‐behaviour are known. In the immune system, T lymphocytes are capable of both secreting and sensing several cytokines and chemokines, such as activated CD4 T‐cells, making both the cytokine interleukin‐2 (IL2) and its high‐affinity receptor component CD25; yet, few cell‐autocrine circuits have been reported so far. Our data now indicate that this signalling module has a distinct cell‐autocrine component in the role it plays in generation and homeostasis of regulatory CD4 T‐cells, and generates major interest in the genesis and consequences of this autocrine loop in immune homeostasis and disease.