Gutward, ho! pDCs in SIV infection

In this issue of Blood, Kwa and colleagues demonstrate that in pathogenic simian immunodeficiency virus (SIV) infection in rhesus macaques, plasmacytoid dendritic cells (pDCs) up-regulate the gut-homing integrin α4β7 and are recruited to the colorectum where they contribute to immune activation.¹ 

In HIV infection and in pathogenic SIV infection of rhesus macaques, a nonnatural host of SIV, there is early, massive depletion of CD4 cells in gastrointestinal tissues and persisting evidence of immune activation and progression to AIDS.²  In contrast, in SIV-infected sooty mangabees, which are natural hosts for SIV, there is a rapid dampening of immune activation despite high levels of ongoing viremia and depletion of mucosal CD4 cells.³  pDCs are recognized as key innate immune players in HIV/SIV infection, with evidence for both depletion/dysfunction as well as chronic activation in HIV/SIV infection.⁴  pDCs are the most potent producers of type I interferons in the body and their frequency and absolute counts are decreased in the blood during both acute and chronic HIV/SIV infection. While in both HIV and pathogenic SIV infection there is initial homing of these cells to lymphoid tissue mediated through their up-regulation of the chemokine receptor CCR7, later in disease these cells are depleted from the peripheral lymphoid tissues as well.⁴  Accompanying this rapid turnover of pDCs in the blood of HIV-infected humans and SIV-infected rhesus macaques, there is immune activation in remaining circulating and lymph node pDCs, with pDCs showing a partially mature phenotype. In addition, up-regulation of IDO and TRAIL on pDCs in HIV infection have been associated with immune suppression and killing of T cells, respectively, although the latter finding is controversial.^5-7 

A number of studies have identified pDCs in gut-associated lymphoid tissue and circulating pDCs express the tissue-trafficking chemokine receptor CCR9.⁸  Although peripheral blood and lymph node pDCs have been studied in the context of acute and chronic SIV/HIV infection, whether pDCs contribute to the chronic immune activation seen in the gut during pathogenic lentiviral infection was previously unknown. In this issue of Blood, Kwa et al demonstrate that peripheral blood pDCs from SIV-infected macaques rapidly up-regulate the gut-homing integrin α4β7 and are recruited to the colorectum where they contribute to immune activation; in vitro, SIV stimulation of these cells resulted in production of proinflammatory cytokines and priming of an antigen-nonspecific T cytotoxic type 1 response.¹  Similarly, the authors demonstrated that while some peripheral blood pDCs from non–HIV-infected human donors express α4β7, this fraction is increased in HIV-infected, antiretroviral-naive individuals. Blockade of the α4β7 integrin using a monoclonal antibody to the β7 integrin in vivo decreased pDC migration to the colorectum of SIV-infected macaques and reduced immune activation at this site as did antiretroviral therapy. Interestingly, in contrast to the results in macaque and human pDCs, Kwa et al found that the pDCs from sooty mangabees did not up-regulate the α4β7 integrin in response to SIV infection, and there were no differences in frequency of pDCs in the blood or colorectum of the infected versus uninfected animals, leading them to suggest that the α4β7 up-regulation by pDCs and their excessive migration may account, in part, for the immune activation in the nonnatural hosts. Curiously, the frequency of α4β7⁺ pDCs and the intensity of expression were much lower in the sooty mangabees than in the macaques and human donors; this could not be attributed to poor antibody recognition of the β7 integrin in the sooty mangabees because their T cells stained for β7 integrin at an intensity similar to that seen in the macaque and human T cells.

Importantly, the up-regulation of the α4β7 integrin on pDCs was not seen in myeloid DCs (mDCs) and, although mDCs were present in the gut of uninfected animals, there was no preferential homing of the mDCs to the colorectum of the infected macaques. Classically, mDCs have been thought to be much more potent antigen-presenting cells than pDCs, although many recent studies have pointed to the importance of pDCs in presentation and cross-presentation of viral antigens.⁹  Intriguingly, Kwa and colleagues also found that when purified DC populations were stimulated with inactivated SIV, the pDCs were much better than mDCs at inducing the proliferation of naive allogeneic CD8 and CD4 T cells. Likewise, pDCs that were sorted from the mesenteric lymph nodes of SIV⁺ macaques could efficiently activate naive T cells, thus providing more evidence that pDCs function both as innate effectors and antigen-presenting cells.

The mechanisms leading to the up-regulation of the β7 integrin on pDCs in the pathogenic versus nonpathogenic SIV infections were not determined in the current study; there was little up-regulation of the α4β7 integrin induced by culture of macaque pDCs with either aldrithio-2–inactivated SIVmac or with the TLR7 agonist imiquimod (both of which induce IFN-α production and pDC activation), leading Kwa et al to conclude that α4β7 is not a pDC activation marker. It will be interesting to determine what does account for the up-regulation of the α4β7 integrin on the pDCs (possibly the diverse cytokine milieu induced by HIV infection?) and whether this is specific to pathogenic HIV/SIV infection or whether it occurs in other acute and chronic viral infections. Likewise, it will be interesting to determine whether the failure of the sooty mangabees to up-regulate α4β7 on pDCs is simply fortuitous or whether this is typical for other nonpathogenic SIV/HIV infections such as in the African green monkey or human elite controllers.

Because pDCs become equipped to migrate to the gut and a sizeable number are already resident in the ileum, gut-associated lymphoid tissue and colorectum and can respond to viral stimulation with vigorous type I interferon,^8,10  it seems logical that their recruitment and activation are normally valuable for host defense against viral infections. Moreover, a recent report has identified a prominent role for gut pDCs and their IFN-α production in mucosal T-independent IgA induction.¹⁰  The point at which the mucosal pDCs tip from being vital for virus control versus dangerous in SIV and HIV infection requires further investigation, and any therapeutic interventions to prevent pathologic pDC activation in the gut will have to be carefully balanced to prevent losing the normal protective roles of these cells.