Phenotypic differences of CD4+ T cells in response to red blood cell immunization in transfused sickle cell disease patients

Alloimmunization against red blood cells (RBCs) is the main immunological risk associated with transfusion in patients with sickle cell disease (SCD). However, about 50–70% of SCD patients never get immunized despite frequent transfusion. In murine models, CD4⁺ T cells play a key role in RBC alloimmunization. We therefore explored and compared the CD4⁺ T‐cell phenotypes and functions between a group of SCD patients (n = 11) who never became immunized despite a high transfusion regimen and a group of SCD patients (n = 10) who had become immunized (at least against Kidd antigen b) after a low transfusion regimen. We studied markers of CD4⁺ T‐cell function, including TLR, that directly control lymphocyte function, and their spontaneous cytokine production. We also tested responders for the cytokine profile in response to Kidd antigen b peptides. Low TLR2/TLR3 expression and, unexpectedly, strong expression of CD40 on CD4⁺ T cells were associated with the nonresponder status, whereas spontaneous expression of IL‐10 by CD4⁺ T cells and weak Tbet expression were associated with the responder status. A Th17 profile was predominant in responders when stimulated by Jb^k. These findings implicate CD4⁺ T cells in alloimmunization in humans and suggest that they may be exploited to differentiate responders from nonresponders.