Dissociation of CD154 and Cytokine Expression Patterns in CD38+ CD4+ Memory T Cells in Chronic HIV-1 Infection

Abstract

Expression of the activation antigen CD38 on T cells is a strong predictor of the risk of HIV disease progression, but it is not known whether CD38 is a marker or mediator of dysfunction. We examined the relationship between CD38 expression and responses to T-cell receptor stimulation in central memory and effector memory CD4+ T cells in HIV-infected persons and in healthy controls. Basal CD38 expression was preserved by blocking golgi transport with brefeldin A. Intracellular expression of interleukin 2, interferon γ, and CD154 was measured after stimulating peripheral blood mononuclear cells with the superantigen staphylococcal enterotoxin B with or without anti-CD28 costimulation. Interferon-γ responses were comparable or increased in stimulated CD38+ memory cells, and the interleukin 2 responses of costimulated CD38+ central memory cells were decreased in HIV infection. In CD38+ cells and especially in CD38+ cells of HIV-infected persons, stimulated memory cells more often failed to express CD154 (CD40 ligand) when induced to express cytokine. A dissociated cytokine and CD154 expression by memory CD4 T cells may impair interactions between T cells and antigen-presenting cells, contribute to impaired immunity and help explain the relationship between CD38 expression and disease progression in chronic HIV infection.

Cycling Memory CD4+T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

“…We also show here that in vitro exposure to the common gammachain cytokines IL-2, IL-7, and IL-15 also increases OX40 expression, while exposure to LPS or to an inflammatory cytokine (IL-6, IL-1␤, or IFN-␣) does not. In earlier work, we showed that the induction of CD40L expression after TCR engagement is impaired in HIV infection (19) but that this is not the case for induction of OX40. The relatively lower level of expression of both OX40 and CD40L on cycling CD4 ϩ T cells in HIV infection suggests that the relative contributions to memory CD4 ϩ T cell cycling of TCR engagement and responses to homeostatic cytokines may be lower in subjects with HIV infection than in healthy subjects, although it is possible that the more activated (CD38 ϩ ), more exhausted (PD-1-positive) cycling cells in HIV infection may be less capable of upregulating OX40 expression or that OX40 expression is lost more rapidly in HIV infection.…”

“…Our earlier work indicated that intracellular CD40L expression by memory CD4 ϩ T cells is impaired in HIV infection after TCR stimulation in vitro (19). To ascertain whether the reduced expression of OX40 on cycling memory CD4 ϩ T cells in HIV ϩ donors (Fig.…”

In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4+ T Lymphocytes

“…Immediately after plating, we collected 100 µL of conditioned media from all samples. Naïve CD4 + T lymphocytes were subsequently activated using 30 µL soluble SEB (1 µg mL −1 , kindly provided by Michael J. Rosen, MD, MSCI, Cincinnati Children's Hospital Medical Center) and 30 µL anti-CD28 (10 µg mL −1 , BD Biosciences, San Jose, CA) 25 . Following 6 hours of incubation, at 37 °C, 100 µL of reconditioned media was collected from all samples and stored at −80 °C (Fig.…”

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

“…There is, however, scant evidence linking this marker or its function to dysfunction of T cells that express it [14,15]. We previously identified a dissociation of CD154 (CD40L) expression and cytokine production in CD38 + memory CD4 + T cells from HIV-infected persons after super-antigen Staphylococcus aureus enterotoxin B (SEB)-induced polyclonal activation [15].…”

“…There is, however, scant evidence linking this marker or its function to dysfunction of T cells that express it [14,15]. We previously identified a dissociation of CD154 (CD40L) expression and cytokine production in CD38 + memory CD4 + T cells from HIV-infected persons after super-antigen Staphylococcus aureus enterotoxin B (SEB)-induced polyclonal activation [15]. Since SEB-induced activation may not reflect the same physiologic events as cognate peptide responses [16], and may include cells with a more diverse maturation history, we investigated here if CD38 expression on central memory (T CM ) or effector memory (T EM ) CD4 + T cells was associated with impaired expression of interleukin (IL)-2, interferon (IFN)-γ or CD154 in response to antigens of the prevalent opportunistic pathogen cytomegalovirus (CMV).…”