Relinquishing and Governing the Volatile: The Many Afghanistans and Critical Research Agendas of NATO's Governance

This article invites academics and policy analysts to examine the mechanisms and legacy of NATO's security and development governance of Afghan social spaces by using critical theory concepts. It argues that such scholarly endeavors are growing in importance as the United States and NATO gradually pull their troops out of Afghanistan. Thus, the article suggests a broad twofold research agenda. First, it points out that researching social spaces such as towns, villages, marketplaces, and neighborhoods beyond the realm of intergovernmental politics can lead to thick descriptions of how such places have been governed from within by agents external to them. Second, the study argues for a multifaceted examination of instruments, strategies, and institutions of security governance, its conduct and social effects by deploying critical and Foucauldian concepts such as the rationality and apparatuses of power relations. Thereby, it proposes an inquiry into Provincial Reconstruction Teams and Afghan National Security Forces as spatially and temporally specific apparatuses of surveillance and security

Anti-CD4-mediated selection of Treg in vitro – in vitro suppression does not predict in vivo capacity to prevent graft rejection

Regulatory T cells (Treg) have been shown to play a role in the prevention of autoimmune diseases and transplant rejection. Based on an established protocol known to generate alloantigen reactive Treg in vivo, we have developed a strategy for the in vitro selection of Treg. Stimulation of unfractionated CD4+ T cells from naive CBA.Ca (H2k) mice with C57BL/10 (H2b) splenocytes in the presence of an anti-CD4 antibody, YTS 177, resulted in the selection of Treg able to inhibit proliferation of naive T cells. In vivo, the cells were able to prevent rejection of 80% C57BL/10 skin grafts when co-transferred to CBA.Rag–/– mice together with naive CD45RBhighCD4+ cells. Purification of CD62L+CD25+CD4+ cells from the cultures enriched for cells with regulatory activity; as now 100% survival of C57BL/10 skin grafts was achieved. Furthermore, differentiation of Treg could be also achieved when using purified CD25–CD4+ naive T cells as a starting population. Interestingly, further in vitro expansion resulted in a partial loss of CD4+ cells expressing both CD62L and CD25 and abrogation of their regulatory activity in vivo. This study shows that alloantigen stimulation in the presence of anti-CD4 in vitro provides a simple and effective strategy to generate alloreactive Treg

Periodic Accumulation of Regulatory T Cells in the Uterus: Preparation for the Implantation of a Semi-Allogeneic Fetus?

BACKGROUND: Naturally occurring Foxp3(+)regulatory T cells play an important role in the inhibition of an immunological attack of the fetus. As implantation of the fetus poses an immediate antigenic challenge, the immune system has to prepare itself for this event prior to implantation. METHODOLOGY AND PRINCIPAL FINDINGS: Here, we show using quantitative RT-PCR and flow cytometry that regulatory T cells accumulate in the uterus not only during pregnancy, but also every time the female becomes fertile. Their periodic accumulation is accompanied by matching fluctuations in uterine expression of several chemokines, which have been shown to play a role in the recruitment and retention of regulatory T cells. CONCLUSIONS/SIGNIFICANCE: The data lead us to propose that every time a female approaches estrus, regulatory T cells start to accumulate in the uterus in preparation for a possible implantation event. Once pregnancy is established, those regulatory T cells that have seen alloantigen need to be retained at their site of action. Whilst several chemokines appear to be involved in the recruitment and/or retention of regulatory T cells during estrus, in pregnancy this role appears to be taken over by CCL4

Combined insulin B:9-23 self-peptide and polyinosinic-polycytidylic acid accelerate insulitis but inhibit development of diabetes by increasing the proportion of CD4+Foxp3+ regulatory T cells in the islets in non-obese diabetic mice.

Insulin peptide B:9-23 is a major autoantigen in type 1 diabetes. Combined treatment with B:9-23 peptide and polyinosinic-polycytidylic acid (poly I:C), but neither alone, induce insulitis in normal BALB/c mice. In contrast, the combined treatment accelerated insulitis, but prevented diabetes in NOD mice. Our immunofluorescence study with anti-CD4/anti-Foxp3 revealed that the proportion of Foxp3 positive CD4(+)CD25(+) regulatory T cells (Tregs) was elevated in the islets of NOD mice treated with B:9-23 peptide and poly I:C, as compared to non-treated mice. Depletion of Tregs by anti-CD25 antibody hastened spontaneous development of diabetes in non-treated NOD mice, and abolished the protective effect of the combined treatment and conversely accelerated the onset of diabetes in the treated mice. These results indicate that poly I:C combined with B:9-23 peptide promotes infiltration of both pathogenic T cells and predominantly Tregs into the islets, thereby inhibiting progression from insulitis to overt diabetes in NOD mice

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Protease Activated Receptor 4 as a Novel Modulator of Regulatory T Cell Function

Regulatory T cells (Tregs) are a subpopulation of T cells that maintain immunological tolerance. In inflammatory responses the function of Tregs is tightly controlled by several factors including signaling through innate receptors such as Toll like receptors and anaphylatoxin receptors allowing an effective immune response to be generated. Protease-activated receptors (PARs) are another family of innate receptors expressed on multiple cell types and involved in the pathogenesis of autoimmune disorders. Whether proteases are able to directly modulate Treg function is unknown. Here, we show using two complimentary approaches that signaling through PAR-4 influences the expression of CD25, CD62L and CD73, the suppressive capacity, and the stability of Tregs, via phosphorylation of FoxO1 and negative regulation of PTEN and FoxP3. Taken together, our results demonstrate an important role of PAR4 in tuning the function of Tregs and open the possibility of targeting PAR4 to modulate immune responses

Bidirectional homing of Tregs between the skin and lymph nodes

Although several homing receptors are known to be differentially expressed by Tregs in lymphoid tissues compared with those found in peripheral tissues, it remains unclear whether these cells traffic between the two locations. In this issue of the JCI, Tomura et al. report steady-state Treg migration from the skin to draining LNs in mice. Furthermore, they report that not only does skin inflammation exacerbate LN-directed Treg homing, it also triggers reverse circulation of Tregs from LNs to skin, whereby these cells contribute to regulation of the immune response. These results now form a new framework for our understanding of Treg homing