Macrophages

Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. Marriott, H. M. et al. J. Clin. Invest. 115, 359–368 (2005).

On bacterial infection, macrophages must initially maintain viability in the face of toxic bacterial products, thereby contributing to innate immunity, but subsequently, they must undergo apoptosis to facilitate bacterial clearance. So, what mediates this switch from macrophage survival to apoptosis? Marriott et al. show that, after pneumococcal infection, macrophages initially upregulate expression of the anti-apoptotic BCL-2-family member MCL1 and survive for up to 14 hours. Then, expression of full-length MCL1 protein is reduced, and expression of a 34-kDa splice variant, MCL1exon-1, is upregulated, which triggers activation of pro-apoptotic pathways. Consistent with a key role for MCL1 in regulating macrophage viability, Mcl1-transgenic mice clear pneumococci from the lungs less efficiently than control mice.

HIV

Impaired base excision repair and accumulation of oxidative base lesions in CD4+ T cells of HIV-infected patients. Aukrust, P. et al. Blood 10 Feb 2005 (10.1182/blood-2004-11-4272).

Increased oxidative stress contributes to the pathogenesis of HIV infection, by causing endogenous DNA damage. Because the base-excision repair pathway has a crucial role in removing oxidative DNA damage, the authors compared the levels of DNA damage and the activity of the DNA-glycosylase repair enzymes in T cells from HIV-infected patients and controls. They observed that CD4+ T cells from HIV-infected patients had higher levels of 8-oxoguanine (a marker of oxidative DNA damage) and decreased glycosylase activity compared with controls. By contrast, the 8-oxoguanine levels in CD8+ T cells were similar in both HIV-infected patients and controls. Importantly, highly active antiretroviral therapy increased glycosylase activity and normalized 8-oxoguanine levels in CD4+ T cells.

Structure

Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45. Nam, H.-J. et al. J. Exp. Med. 201, 441–452 (2005).

The receptor protein tyrosine phosphatase (PTP) CD45 has two PTP domains D1 and D2, only one of which (D1) is catalytically active. Two crystal structures of the native CD45 D1–D2 domain solved by Nam et al. indicate that D1 and D2 have almost identical structures. However, substrate-bound crystal structures of this domain showed that phosphorylated peptides bind the catalytically active D1 but not the catalytically inactive D2. Despite this, the structure of D2 provides support for the hypothesis that it is involved in substrate recruitment. The structures also indicate that the D1–D2 domain does not dimerize, which is incompatible with the idea that CD45 PTP activity is inhibited by dimerization.