The 'Making-of' B lymphocytes is one of the most thoroughly studied cell developmental systems in mammals. Still, our understanding of B cell development and survival in the periphery remains incomplete.
Recently we discovered that mice with an inactivating mutation in the intramembrane protease SPPL2A unexpectedly exhibited profound humoral immunodeficiency and specifically lacked mature B cells, phenotypically mirroring BAFF deficient mice. Surviving B cells were characterized by low surface BAFFR and BCR expression, making them less responsive to extracellular stimuli in vitro.
As BCR and BAFFR are important regulators for peripheral B cell survival, we tested whether SPPL2A deficient B cells are unable to mature due to a survival defect or developmental arrest. Mature B cell accumulation, but not BAFFR and BCR expression, could be rescued by over-expression of the BAFF-induced pro-apoptotic protein BCL2, indicating a survival defect of mature B cells.
On a molecular level we identified SPPL2A as the long sought-after, final enzyme in the sequence of CD74 (MHC II invariant chain) cleaving proteases. SPPL2A deficiency blocked the ultimate step of CD74 degradation, causing a dramatic build-up of short p8-CD74 peptide fragments, the product of Cathepsin S processing in the MHCII antigen presenting compartment. Accumulation of p8-CD74 was responsible for the cellular phenotype as deletion of CD74 in SPPL2A deficient animals reconstituted mature B cell numbers to levels seen in mice solely deficient in CD74, and also restored surface BCR and BAFFR expression.
Our findings highlight an important role for SPPL2A in the final degradation steps of CD74-invariant chain and B cell survival.