CD6is alymphocyte-specific scavenger receptor expressedon adaptive (T) andinnate (B1a,NK)immunecells,which is involved in bothfine-tuningof lymphocyteactivation/differentiation and recognition of bacterial-associated molecular patterns (i.e., lipopolysaccharide). However, evidence on CD6’s role in the physiological response to bacterial infection was missing. Our results show that induction of monobacterial and polymicrobial sepsis in Cd6 / mice results in lower survival rates and increased bacterial loads and pro-inflammatory cytokine levels. Steady state analyses ofCd6 mice show decreased levels of natural polyreactive antibodies, concomitant with decreased cell counts of spleen B1a and marginal zone B cells. Adoptive transfer of wild-type B cells and mouse serum, as well as a polyreactive monoclonal antibody improve Cd6 / mouse survival rates post-sepsis. These findings support a nonredundant role forCD6intheearly responseagainst bacterial infection, throughhomeostatic expansion and functionality of innate-related immune cells.