Wednesday, October 31, 2007

Adaptive Control of Innate Immunity

Innate immunity controls infections while the adaptive immune response develops. In the absence of T cells, infections that kill the host were thought to result from an uncontrolled infection. However, Kim and colleagues demonstrate here that the adaptive immune response is also necessary to control the innate immune response. They show that host death can result from an uncontrolled innate response that occurs in the absence of an adaptive immune response.
Triggering the innate immune receptor TLR3 with poly(I:C), a double stranded RNA that mimics viruses, produced a destructive and potentially lethal “cytokine storm”. This fatal reaction required Natural Killer (NK) cells and TNF. The figure is a portion of figure 4 showing the response of immune deficient animals: panel e shows that abrogating TNF signaling but not immunoglobulin signaling is protective and panel f shows that NK cell depletion is protective. As the authors note, these findings might be also important for understanding the responses of “individuals with congenital or acquired immune deficiency”.
Kim et al. Nat Med. 2007 Nov;13(10):1248. "Adaptive immune cells temper initial innate responses".

Monday, October 15, 2007

Shear forces trigger T cell adhesion

At sites of inflammation, T lymphocytes bind to activated endothelium and move from the bloodstream into lymph nodes. Recruited T cells remain highly motile within the lymph node, scanning many dendritic cells and other antigen-presenting cells for cognate antigen. T cell motility is stimulated by chemokines, which can also promote adhesion by activating integrins.

Woolf and colleagues observed that many cells, including T cells themselves, express the same adhesion molecules and asked how premature arrest and clumping was avoided. To delineate the contributions of chemokines and adhesion molecules, they coated surfaces with CCL21, ICAM-1, or VCAM-1 and observed T cells moving on these surfaces. They found that surface-bound CCL21 stimulated T cell motility but soluble CCL21 did not. Although CCL21 also induced clustering of LFA-1 and VLA-4, these integrins did not mediate adhesion to their ligands ICAM-1 and VCAM-1. However, when T cells were exposed to shear stress, they rapidly developed strong adhesion to ICAM-1 or VCAM-1 (Figure). Video microscopy of T cells and lymph nodes cells obtained from mice deficient in adhesion molecules provided additional support for their conclusion that integrin-mediated adhesion, which is crucial to T cell recruitment from the bloodstream, is 'silenced' within the lymph node due to the absence of shear force.

Woolf et al. Nat Immunol. 2007 Oct;8(10):1076-85. Lymph node chemokines promote sustained T lymphocyte motility without triggering stable integrin adhesiveness in the absence of shear forces