Role of 4-1BB Receptor in the Control Played by CD8+ T Cells on IFN-γ Production by Mycobacterium tuberculosis Antigen-Specific CD4+ T Cells

BACKGROUND: Antigen-specific IFN-gamma producing CD4(+) T cells are the main mediators of protection against Mycobacterium tuberculosis infection both under natural conditions and following vaccination. However these cells are responsible for lung damage and poor vaccine efficacy when not tightly controlled. Discovering new tools to control nonprotective antigen-specific IFN-gamma production without affecting protective IFN-gamma is a challenge in tuberculosis research. METHODS AND FINDINGS: Immunization with DNA encoding Ag85B, a candidate vaccine antigen of Mycobacterium tuberculosis, elicited in mice a low but protective CD4(+) T cell-mediated IFN-gamma response, while in mice primed with DNA and boosted with Ag85B protein a massive increase in IFN-gamma response was associated with loss of protection. Both protective and non-protective Ag85B-immunization generated antigen-specific CD8(+) T cells which suppressed IFN-gamma-secreting CD4(+) T cells. However, ex vivo ligation of 4-1BB, a member of TNF-receptor super-family, reduced the massive, non-protective IFN-gamma responses by CD4(+) T cells in protein-boosted mice without affecting the low protective IFN-gamma-secretion in mice immunized with DNA. This selective inhibition was due to the induction of 4-1BB exclusively on CD8(+) T cells of DNA-primed and protein-boosted mice following Ag85B protein stimulation. The 4-1BB-mediated IFN-gamma inhibition did not require soluble IL-10, TGF-beta, XCL-1 and MIP-1beta. In vivo Ag85B stimulation induced 4-1BB expression on CD8(+) T cells and in vivo 4-1BB ligation reduced the activation, IFN-gamma production and expansion of Ag85B-specific CD4(+) T cells of DNA-primed and protein-boosted mice. CONCLUSION/SIGNIFICANCE: Antigen-specific suppressor CD8(+) T cells are elicited through immunization with the mycobacterial antigen Ag85B. Ligation of 4-1BB receptor further enhanced their suppressive activity on IFN-gamma-secreting CD4(+) T cells. The selective expression of 4-1BB only on CD8(+) T cells in mice developing a massive, non-protective IFN-gamma response opens novel strategies for intervention in tuberculosis pathology and vaccination through T-cell co-stimulatory-based molecular targeting

Mitteilungen des Oberhessischen Geschichtsvereins Gießen 31 (1933)

Taeger, Fritz: Das römische Germanien und die Reichs-Politik Mittermaier, Franz Paul: Studien zur Territorialgeschichte der südlichen Wetterau Noack, Friedrich: Landgraf Philipps Glaubenswechsel und Eheschließung 1693 Bericht über die im Oberhessischen Geschichtsverein gehaltenen Vorträge Winter 1932/33: - Schulte, Otto: Über den Hüttenberg - Roloff, Gustav: Hessen im Jahre 1866 - Mayer, Theodor: Die Wetterau in der älteren deutschen Geschichte - Ebel, Karl: Die Anfänge der Stadt Gieße

Circadian variation in the circulatory responses to exercise: relevance to the morning peaks in strokes and cardiac events

Sudden cardiac and cerebral events are most common in the morning. A fundamental question is whether these events are triggered by the increase in physical activity after waking, and/or a result of circadian variation in the responses of circulatory function to exercise. Although signaling pathways from the master circadian clock in the suprachiasmatic nuclei to sites of circulatory control are not yet understood, it is known that cerebral blood flow, autoregulation and cerebrovascular reactivity to changes in CO(2) are impaired in the morning and, therefore, could explain the increased risk of cerebrovascular events. Blood pressure (BP) and the rate pressure product (RPP) show marked ‘morning surges’ when people are studied in free-living conditions, making the rupture of a fragile atherosclerotic plaque and sudden cardiac event more likely. Since cerebral autoregulation is reduced in the morning, this surge in BP may also exacerbate the risk of hemorrhagic and ischemic strokes in the presence of other acute and chronic risk factors. Increased sympathetic activity, decreased endothelial function, and increased platelet aggregability could also be important in explaining the morning peak in cardiac and cerebral events but how these factors respond to exercise at different times of day is unclear. Evidence is emerging that the exercise-related responses of BP and RPP are increased in the morning when prior sleep is controlled. We recommend that such ‘semi-constant routine’ protocols are employed to examine the relative influence of the body clock and exogenous factors on the 24-h variation in other circulatory factors