CD5, CD28 and CD40 as interconnected co‐stimulatory/immune‐modulators of T cells responses in the NOD, NOR and BALB mouse strains

Abstract

Previously we have illustrated a significant expansion of the CD4+CD40+ T cell subset in both mouse and human type 1‐diabetic subjects as compared to non‐autoimmune controls. To mechanistically associate disease onset with the observed expansions in this cell population we have suggested that CD40 engagement promotes alteration of peripheral TCR (revision) as well as induces the anti‐apoptotic protein BcL‐xL. Recently it has been documented that CD40 can serve as co‐stimulatory molecule further enhancing the classical signal 1 & 2 activation stimulus of CD3 & CD28 in the C57BL/6 model of CIA illustrating that CD40 signaling has a direct effect on effector T cell function. Here we elaborate on the notion of CD40 as a co‐stimulatory molecule illustrating that in NOD, NOR and BALB, CD40 dampens the IL‐2 response instigated by CD3&CD28 while elevating IL‐2 response induced by the unconventional stimulus of CD3&CD5, revealing CD40 to have a role as an immunomodulator whose effects are dependent upon activation conditions and intimately connected with signals propagated through CD3, CD28 and CD5. Importantly we illustrate that CD5 a molecule long associated with augmentation of TCR signaling, reverses the inhibitory effects of CD40. Additionally we observe that CD5 activation in combination with signals from CD3, CD28 and CD40 induces surface expression of CD40 on the surface of previously CD40 negative T cells.