Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

CD4+Tm cells in children with T1D and their siblings show increased sensitivity to activation induced cell death (#67)

Michael L Bian 1 , David Munster 1 , Mark Harris 2 , Andrew Cotterill 2 , Slavica Vuckovic 1 3
  1. Mater Research, Translational Research Institute, Brisbane, QLD, Australia
  2. Mater Children's Hospital, Brisbane, QLD, Australia
  3. Queensland Institute of Medical Research, Berghofer Medical Research Institute, Brisbane, QLD, Australia

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease, often presented in children. Unwanted autoreactive CD4+ memory T (CD4+Tm) cells have been proposed to play a central role in driving the pathological autoimmune beta cell damage in T1D.  Because activation induced cell death (AICD) is responsible for elimination of auto-reactive T cells, increased AICD should lead to greater elimination of auto-reactive CD4+Tm cells and be protective against autoimmune beta cell damage. We evaluated whether AICD was maintained in blood CD4+Tm cells in T1D children, their diabetes-free siblings and age-/sex-matched controls. Here we show that both T1D and sibling were mildly lymphopenic, compared to controls (p<0.001). T1D children, but not the siblings, had fewer absolute number and lower frequency of blood CD4+Tm cells than controls. The CD4+Tm cell reduction in T1D was confined within effector memory (CD45RO+CD62L-) but not central memory (CD45RO+CD62L+) CD4+T cells. To study AICD in CD4+Tm cells in response to TCR stimulation, we stimulated purified blood CD4+Tm cells ex vivo with anti-CD3/anti-CD28 in the presence of autologous serum. There was no difference in proliferation, but both T1D and sibling CD4+Tm cells underwent higher rates of AICD than controls (p=0.004), and the AICD-prone cells were predominantly effector memory CD4+T cells. The increased AICD in T1D and sibling CD4+Tm cells were associated with higher surface expression of death pathway molecules, Fas and FasL. Replacing autologous with allogeneic serum did not change the AICD rates. The increased AICD in T1D CD4+Tm cells correlated with their lowered blood count (p=0.023), but there was no such correlation in siblings.

Our data suggest CD4+Tm cells from both T1D and siblings have higher propensity for AICD upon TCR stimulation. However, this does not explain the lowered blood CD4+Tm counts observed only in T1D, suggesting there are other mechanisms influencing CD4+Tm cell turnover in T1D.