Here, we retrieved (i) de novo differentially scGRNs driven by Nur77 and KDM2B in exhausted CD8+ T cells; (ii) revealed changes in gene networks regulated by E2F members of host cells in response to infection; (iii) and found an increase in scGRNs related to immunity and neuronal excitation of brain cell subtypes susceptible to autism. Here, KDM2B is linked to infection.