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.