We have performed an initial screening of the phenotype caused by null-mutation of the gene encoding the C2 catalytic subunit of PKA in mice. The C2 subunit is enriched in immune cells such as T-, B- and NK cells. We found that PKA catalytic activity was increased in cells isolated from immune organs such as thymus, spleen and LN. Moreover, we observed anti-CD3/CD28-induced increased proliferation of cells isolated from the spleen and thymus but not LN. Using flow cytometry we demonstrated that the relative number of B cells was reduced in the LN, whereas in the spleen B cells were reduced and NK cells were increased. The relative number of the different T cells subsets was not changed in the thymus whereas in the LN and spleen CD4+ cells were significantly increased compared to wt mice. This was most probably due to a relative increase in Th1 lineage since the relative number of Th2 cells appeared unaltered and Treg cells (CD25+FoxP3+) were significantly reduced in the LN and spleen. By monitoring the relative expression of the homing receptor CD62L and the activation marker CD69 we found that C2 null-mutation may abrogate the development of T cells from naïve to memory cells, implying that the C2 mice are devoid or harbor reduced number of memory T cells. Taken together, our results demonstrate that C2 KO results in a complex phenotype associated with the immune system. A reduction in the Treg which are engaged in the maintenance of immunological self-tolerance and suppressive control of excessive immune responses to foreign antigens might imply that C2 KO animals may develop autoimmune disease and/or might have a different susceptibility to tumor development. Moreover, a block in the development of memory T cells might imply that the C2 KO mice are more susceptible to infections. To what extent one or both of these suggestions are true for the C2 KO will need further investigation.