Pim kinases significantly impact humoral immune responses (IRM12P.648)

The Provirus Integration site for Moloney murine leukemia virus (Pim) family of oncogenic serine/threonine kinases regulates a variety of metabolic functions in hematopoietic cells and lymphocytes. We examined the importance of Pim kinases in B cell activation following antigen stimulation. Humoral immune responses were significantly impaired in Pim 1 and 2 deficient mice (Pim 1 -/- 2 -/- ) T cell dependent responses were compromised while T cell independent type 1 and 2 antigen responses were virtually absent. Humoral deficiencies were owing to reduced production of antibody secreting cells due to the diminished induction of BLIMP-1 expression. The central role of Pim in these responses is consistent with our observation that Pims are induced downstream of multiple B cell activation receptors including CD40, BCR, and TLR4. We suggest that Pim 1 and 2 dependent signaling pathways are involved in B cell activation and their loss requires increased signaling through other pathways to reach an activation threshold. This hypothesis is further supported by the initial higher affinity of BCRs on Pim deficient B cells activated in a TD response and their inability to proliferate or undergo isotype switching in culture at the same rate as WT B cells when activator concentrations are decreased. Taken together, these data demonstrate a critical role for Pim kinases in affinity maturation, isotype switching, proliferation and the production of antibody secreting cells by B lymphocytes. .