Cytomegalovirus-specific responses of CD38+ memory T cells are skewed towards IFN-γ and dissociated from CD154 in HIV-1 infection

Abstract

Objective Despite the strong correlation of T-cell CD38 expression with HIV disease progression, evidence linking CD38 expression and dysfunction at the single cell level is scant. Since CD38+ memory CD4+ T cells, especially those from HIV-infected persons, fail to induce CD154 (CD40L) while responding to a superantigen with interferon (IFN)-γ or interleukin (IL)-2, we aimed to determine if recall responses to cytomegalovirus (CMV) were similarly affected in the CD38+ memory CD4+ T-cell subpopulation. Design and methods Peripheral blood mononuclear cells from HIV+ patients and healthy controls were incubated 14 h with CMV antigens, the superantigen Staphylococcus aureus enterotoxin B or medium, and labeled for identification of central memory (TCM) and effector memory (TEM) CD4+ T cells, and for the intracellular detection of induced CD154, IFN-γ and/or IL-2 by flow cytometry. Results Compared with CD38− cells, CD38+ TCM cells from patients had less CD40L induction after CMV stimulation, and increased IFN-γ response. Patients’ CD38+ TEM cells showed a lower IL-2 response, and tended to have a greater IFN-γ response, in which CD154 induction frequently failed. CMV-specific responses of patients’ CD38+ TCM and TEM cells were dominated by IFN-γ, and almost all IL-2+ cells co-expressed IFN-γ. IL-2 responses to the polyclonal activator S. aureus enterotoxin B were also significantly less frequent among CD38+ TCM and TEM cells than in CD38− cells. Conclusion Patients’ CD38+ memory CD4+ T-cell responses to CMV favor the effector cytokine IFN-γ over IL-2, in the context of deficient CD154 induction, which may limit co-stimulation, proliferation and survival.

A transcriptome-based model of central memory CD4 T cell death in HIV infection

“…We asked if differential gene expression by patients’ and controls’ T CM cells reflected greater differentiation of patients’ cells (towards effector stages) [23, 24]. Using the criteria defined in methods (Log 2 FC ≥ |0.5| and Log (odds) > 0) we looked in the whole transcriptome for all differentially expressed genes in the following pair-wise comparisons of CD4 T cell subpopulations from controls: T CM vs. T N , T EM vs. T CM, and T EM vs. T N (arrows a, b and c in Fig.…”

“…Our previous studies on activated (CD38 + ) T CM cells, particularly those from HIV-infected patients, showed IFN-γ-skewed cytokine responses that were un-connected to CD40L induction, along with a lowered IL-2 production [23, 24]. Given this functionality, T CM cells seemed differentiated towards an effector fate [40, 42, 43, 91, 92].…”

“…Additionally, CD4 T cells from patients with HIV could be intrinsically altered, as suggested by the limited proportion of HIV-infected patients recovering their pre-infection CD4 T cells counts under virus-controlling antiretroviral therapy [22]. In this regard, we have found intrinsic dysfunctions in activated T CM cells from HIV-infected patients, as a lowered IL-2 response and CD40L induction after T cell receptor (TCR)-mediated stimulation [23, 24], which could decrease their proliferative, differentiation, and survival capacities.…”

Avaliação do efeito das enterotoxinas estafilocócicas tipos A e B em células Th17, Th22 e CD38+ na dermatite atópica do adulto

“…Indivíduos com DA apresentam redução da função dos TLR e falha nesse processo de proteção, bem como nos peptídeos antimicrobianos, promovendo uma predisposição maior às infecções cutâneas, principalmente pelo S. aureus20 . As principais alterações relacionadas à disfunção da imunidade inata na DA estão esquematizadas na Figura 1.A expressão de CD38 nas células T destaca-se dentre os biomarcadores da ativação crônica na infecção pelo HIV, com poucas evidências ligando este marcador com a disfunção das células T61 . Uma vez que a DA representa dermatose com colonização crônica por S. aureus, objetivamos avaliar a expressão de CD38 em células T CD4+/CD8+ polifuncionais (IL-17A, IL-22, IFN-, MIP-1 e TNF) induzida por enterotoxinas estafilocócicas.…”

“…Ionomicina, em comparação com psoríase30 , enquanto outros demonstram níveis elevados de IL-22 em células T CD4+ de pacientes com DA, estimuladas com -toxina de S. aureus e SEB23,24 . infecção pelo HIV61 . Nossos resultados, após estímulos com SEA e SEB e análise das células CD38+, mostraram que: 1) pacientes com DA (ex vivo) possuem células T CD4+ de memória, preservadas na presença de CD38; 2) células T CD4+ de pacientes com DA, sob estímulo com as enterotoxinas estafilocócicas in vitro, associadas à ausência da expressão de CD38, contribuem com cronicidade da doença e a inflamação persistente.…”