Mapping autophagosome contents identifies interleukin-7 receptor-α as a key cargo modulating CD4+ T cell proliferation.
Nat Commun. 2022 Sep 2;13(1):5174. doi: 10.1038/s41467-022-32718-x. PMID: 36055998; PMCID: PMC9440129..
|Authors/Editors:||Zhou D, Borsa M, Puleston DJ, Zellner S, Capera J, Sanderson S, Schifferer M, Hester SS, Ge X, Fischer R, Jostins L, Behrends C*, Alsaleh G*, Simon AK*.|
CD4+ T cells are pivotal cells playing roles in the orchestration of humoral and cytotoxic immune responses. It is known that CD4+ T cell proliferation relies on autophagy, but identification of the autophagosomal cargo involved is missing. Here we create a transgenic mouse model, to enable direct mapping of the proteinaceous content of autophagosomes in primary cells by LC3 proximity labelling. Interleukin-7 receptor-α, a cytokine receptor mostly found in naïve and memory T cells, is reproducibly detected in autophagosomes of activated CD4+ T cells. Consistently, CD4+ T cells lacking autophagy show increased interleukin-7 receptor-α surface expression, while no defect in internalisation is observed. Mechanistically, excessive surface interleukin-7 receptor-α sequestrates the common gamma chain, impairing the interleukin-2 receptor assembly and downstream signalling crucial for T cell proliferation. This study shows that key autophagy substrates can be reliably identified in this mouse model and help mechanistically unravel autophagy’s contribution to healthy physiology and disease.