Partial dysfunction of Treg activation in sickle cell disease

Abstract

Sickle cell disease (SCD) is a chronic inflammatory disease associated with multiple organ damage, chronic anemia, and infections. SCD patients have a high rate of alloimmunization against red blood cells (RBCs) following transfusion and may develop autoimmune diseases. Studies in mouse models have suggested that regulatory T cells (Treg) play a role in alloimmunization against RBC antigens. We characterized the phenotype and function of the Treg cell population in a homogeneous cohort of transfused SCD patients. We found that the distribution of Treg subpopulations differed significantly between SCD patients and healthy blood donors. SCD patients have a particular Treg phenotype, with strong CTLA-4 and CD39 expression and weak HLA-DR and CCR7 expression. Finally, we show that this particular phenotype is related to SCD rather than alloimmunization status. Indeed, we observed no difference in Treg phenotype or function in vitro using autologous feeder cells between strong and weak responders to alloimmunization.

Protective effect of HLA-DQB1 alleles against alloimmunization in patients with sickle cell disease

“…Other possible mediators of suppression may be CD4 + CD25 + FoxP3 + regulatory T cells (Tregs). Although the role of these cells in alloimmunization is not well understood [47, 48], it is known that such cellular component is able to recognize peptide/MHC complexes with greater avidity than the CD4 + CD25 - FoxP3 - T cells [49-51]. Thus, the assumption would be that HLA-DQ molecules present RBC epitopes recognized by T cells with relatively high avidity.…”

The sickle cell mouse lung: proinflammatory and primed for allergic inflammation

“…The presence of increased Treg numbers in the lung and HLN in naive SCD mice as well as the sharp increase in BAL Tregs in AAD SCD mice would seem to predict heightened capacity for regulation and disease suppression. However, there is some evidence that Tregs in SCD display an altered phenotype and may have reduced immunosuppressive capacity, although the latter remains debated 46,47 . Of particular note, alloimmunization associated with frequent blood transfusion, a mainstay of treatment of SCD, may produce dysfunction in both Tregs 46 and regulatory B cells (Bregs) 48 .…”

Red blood cell alloimmunization is influenced by the delay between Toll-like receptor agonist injection and transfusion

“…3,4 Little is known about the role of CD4 + T cells in alloimmunization, 5 except for Treg cells. [6][7][8] Recently, we showed that the phenotype of CD4 + T cells from SCD patients differs according to whether M urine models of red blood cell transfusion show that inflammation associated with viruses or methylated DNA promotes red blood cell alloimmunization. In vaccination studies, the intensity of antigen-specific responses depends on the delay between antigen and adjuvant administration, with a short delay limiting immune responses.…”