Fibroblast-IL-7 feedback drives PDPN + monocytes to restrain CD4 + T cell responses

Summary During immune responses, pro-and anti-inflammatory mechanisms must be balanced to ensure pathogen clearance while limiting tissue damage. Monocyte-derived cells contribute to both processes, yet the underlying regulatory circuits remain incompletely defined. Here, we show that a subset of PDPN+IL-7R+ monocyte-derived cells that impair effector CD4⁺ T cell–mediated control of intracellular pathogens, and thus perpetuate the infection. Fibroblast-derived IL-7 drives this immunosuppressive program, which is up-regulated in response to IFNγ. We thus uncover a cytokine-dependent feedback circuit in which elevated IFNγ induces IL-7 production by fibroblasts, licensing immunosuppressive monocyte-derived cells that restrain CD4⁺ T cell responses. This mechanism links excessive inflammation to immune suppression at the expense of pathogen control. Targeting this feedback loop may enable therapeutic strategies that enhance antimicrobial immunity while preserving tissue integrity. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵15 Lead contact The revised manuscript contains a meta-analysis of published single cell RNAseq data from tumour-associated monocyte-derived cells (Kruse et al., 2023) in the new supplemental figure S2. These data show a PDPN- and IL-7R-expressing subpopulation with a similar expression pattern as the population described in the L. major infection, indicating the presence of these cells beyond sites of infection. The title and summary have been adapted in order to emphasize the more general interest beyond host-pathogen interaction. Reference: Kruse, B., A.C. Buzzai, N. Shridhar, A.D. Braun, S. Gellert, K. Knauth, J. Pozniak, J. Peters, P. Dittmann, M. Mengoni, T.C. van der Sluis, S. Hohn, A. Antoranz, A. Krone, Y. Fu, D. Yu, M. Essand, R. Geffers, D. Mougiakakos, S. Kahlfuss, H. Kashkar, E. Gaffal, F.M. Bosisio, O. Bechter, F. Rambow, J.C. Marine, W. Kastenmuller, A.J. Muller, and T. Tuting. 2023. CD4(+) T cell-induced inflammatory cell death controls immune-evasive tumours. Nature 618:1033-1040. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE228455