IL-4 induces CD22 expression to restrain the effector program of virtual memory T cells

Parasitic helminths induce the production of interleukin-4 (IL-4), which causes the expansion of virtual memory CD8 + T cells (T VM cells), a cell subset that contributes to the control of coinfection with intracellular pathogens. However, the mechanisms regulating IL-4–dependent T VM cell activation and expansion remain ill defined. Here, we used single-cell RNA sequencing of CD8 + T cells to identify pathways that control IL-4–dependent T VM cell responses. Gene signature analysis of CD8 + T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a selective surface marker of IL-4–induced T VM cells. CD22 + T VM cells were enriched for interferon-γ and granzyme A and retained a diverse TCR repertoire while enriched in self-reactive CDR3 sequences. CD22 intrinsically regulated the IL-4–induced CD8 + T cell effector program, resulting in reduced responsiveness of CD22 + T VM cells and regulatory functions to infection and inflammation. Thus, helminth-induced IL-4 drives the expansion and activation of T VM cells that is counterinhibited by CD22.