B cells activation has a pivotal role in developing an effective vaccine as it differentiates into plasma and memory cells that conferred long lasting immunity to the host. Our earlier study established Outer membrane protein A (OmpA) of Shigella flexneri 2a as a potential vaccine candidate against shigellosis and reveals intranasal immunization of mice with OmpA of Shigella flexneri 2a elicits antigen specific IgG & IgA production, highlighting role of B cell activation in OmpA mediated immune response. The present study was undertaken to investigate whether OmpA can affect B cell activation and identify the underlying signalling pathway associated with OmpA induced B cell immune response. We have found that OmpA is recognised by TLR2 on B cell to induce secretion of protective cytokines IL6 & IL10 and promotes increased surface expression of MHCII and CD86 on B cells. After binding to TLR2, OmpA activates downstream signalling molecules like protein tyrosine kinase, phosphorylate ERK1/2 and IκB‐α thus prompting nuclear translocation of NF‐κB in B cells. Moreover we have identified OmpA induced cytokine secretion is dependent on PTKs activity ERK and NF‐kB whereas B cell differention is dependent on PTKs activity and ERK. We have also evaluated the protective efficacy of OmpA in mouse pulmonary model stating that intranasal immunization of mice with OmpA induces strong protective immunity to pulmonary pneumonia as well as robust levels of systemic and mucosal immunity against lethal challenge of four Shigella sp. Collectively, this finding strengthens the implication of OmpA as a candidate vaccine antigen against shigellosis.