CD4⁺ T Cell Profile and Activation Response in Sickle Cell Disease Patients with Osteonecrosis

Abstract

Recent evidence suggests that abnormalities involving CD4+T lymphocytes are associated with the pathophysiology of osteonecrosis (ON); however, few studies have addressed the CD4+T cells in ON related to sickle cell disease (SCD/ON). In addition, T cells producing multiple cytokines simultaneously are often present in the inflammatory milieu and may be implicated in the immune response observed in SCD/ON. In the present study, we aimed to characterize the functional status of CD4+T cells in SCD by simultaneously determining the frequency of IFN-γ+, IL-4+, and IL-17+ CD4+T in cell cultures under exogenous stimuli. Peripheral blood mononuclear cells (PB-MNCs) from 9 steady-state SCD patients, 15 SCD/ON patients, and 19 healthy controls had functional status of CD4+T cells analyzed. Bone marrow mononuclear cells (BM-MNCs) from 24 SCD/ON patients (SCD BM) and 18 patients with ON not related to SCD (non-SCD BM) were also analyzed. We found that PB-MNC of SCD patients with or without ON presented significantly reduced TCD4+, TCD8+, and TCD4+ naïve cell frequencies and increased frequency of circulating CD4+T cells able to simultaneously produce IFN-γ+/IL4+ and IL-17+/IL4+ compared to healthy controls. Conversely, the polyclonal stimulation of BM-MNC induced an increased frequency of CD4+IFN-γ+ and CD4+IL-17+ in SCD BM compared to non-SCD BM. The increased proportion of CD4+ T cells able to produce a broad spectrum of proinflammatory cytokines after a strong stimulus indicates that the immune system in SCD/ON patients presents an expressive pool of partially differentiated cells ready to take on effector function. It is possible that this increased subpopulation may extend to inflammatory sites of target organs and may contribute to the maintenance of inflammation and the pathophysiology of osteonecrosis in sickle cell disease.

In-Depth Immunological Typization of Children with Sickle Cell Disease: A Preliminary Insight into Its Plausible Correlation with Clinical Course and Hydroxyurea Therapy

“…The SCD HU− subgroup showed significantly higher mean leukocyte and neutrophil absolute count and mean CD4+ central memory and effector memory T-cell% count in comparison to controls, while CD3+ (PAN-T) cell% and CD4+ helper T-cell% were, on average, inferior when compared to controls. These results have a counterpart in the literature, where immunophenotyping of SCD patients off therapy was characterized by neutrophilic, lymphocytic and monocytic leukocytosis, along with a prevalence of memory on naïve T cells, interesting in a particular CD8+ subset in a context of T-cell compartment enlargement [ 5 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. However, other immunological features typical of SCD, such as expansions in CD8+ memory T-cell% and CD19+ B-cell% subsets and inversion of the CD4+/CD8+ ratio, were not observed in the SCD HU− subgroup, probably due to the small sample size [ 5 , 20 , 21 ].…”

“…We found that the mean CD4+ central memory T-cell% count was the only independent variable showing a positive correlation with crisis score in the multivariate analysis. This association probably reflects the role of persistent/chronic immune activation sustained by SCD-related inflammatory and infectious susceptibility in the impairment of T-cell regulation of B cells, favoring the differentiation process from naïve to memory T cells and eventually resulting in an immunosenescent-like phenotype [ 5 , 19 , 29 ].…”

“…Eventually, CD4+ effector memory T cell production could be favored by a persistent secondary immune system response due to both infectious susceptibility and IFN-γ-related effects of memory NK cells, creating a pool of activated T-clones ready to take on effector functions [ 19 ]. While the CD4+ central memory T-cell% population was significantly expanded in the SCD HU− subgroup, it showed normal values in the SCD HU+ subgroup; thus, considering its aforementioned clinical implication in terms of crisis score, it could be used as a biomarker indicative of HU effectiveness.…”

“…Moreover, few studies in the literature have taken into account the SCD patients’ immunophenotypical characterization and the potential impact of specific treatments on the immune system, with a total lack of pediatric study analyzing both humoral and cellular immunity of SCD-related hypo-/a-splenic individuals [ 15 , 16 , 17 , 18 , 19 ].…”

Role of C-X-C motif chemokine ligand 14 promoter region DNA methylation and single nucleotide polymorphism in influenza A severity

“…Neutrophil represented the most plentiful class of cells in immune system, and they were migrated in lung epithelial cells infected by influenza viruses [22]. T lymphocyte subpopulation was generated during inflammatory reaction, and it was closely related to immune response [23]. T lymphocyte subpopulation was exhausted in lymphoid organs and peripheral blood infected with H1N1 to inhibit adaptive immune response [24].…”