Can Langerhans cell UV injury and dendritic cell infection by immunodepressive viruses induce immunologic tolerance? Second part: immunologic tolerance in AIDS

In the first part of the present editorial [1], we recalled experimental and clinical data demonstrating that 1) UV, via their effects on Langerhans cells, and 2) some so-called immunodepressive viruses, such as measles, lymphocytic choriomeningitis agents, and some animal retroviruses, via their action on dendritic cells, can induce tolerance in some conditions concerning immunologic parameters and/or the antigen(s). We present in this second part of the editorial a commentary on patients treated at the AIDS phase of HIV-1 infection for 3.5 to 8 years. Among them, one has been submitted before and at the beginning of our treatment, for a psoriasis, to a PUVA irradiation, at the dose of 214.5 J (spectrum 230-320). We were present at the end of this irradiation to see the disappearance of his blood CD4 and of his suppressor T cells. Comparing his data with those of other patients of the cohort similarly treated, we have found arguments to consider that this UV-victim patient has presented for the 6 years of his clinically excellent survival and still presents manifestations of immunologic tolerance towards a fraction of his HIV-1 population.     

Lymph node stromal cells acquire peptide–MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance

Dendritic cells (DCs), and more recently lymph node stromal cells (LNSCs), have been described to tolerize self-reactive CD8⁺ T cells in LNs. Although LNSCs express MHCII, it is unknown whether they can also impact CD4⁺ T cell functions. We show that the promoter IV (pIV) of class II transactivator (CIITA), the master regulator of MHCII expression, controls endogenous MHCII expression by LNSCs. Unexpectedly, LNSCs also acquire peptide–MHCII complexes from DCs and induce CD4⁺ T cell dysfunction by presenting transferred complexes to naive CD4⁺ T cells and preventing their proliferation and survival. Our data reveals a novel, alternative mechanism where LN-resident stromal cells tolerize CD4⁺ T cells through the presentation of self-antigens via transferred peptide–MHCII complexes of DC origin.Self-reactive T cells that escape thymic negative selection are kept in check by peripheral tolerance mechanisms that include T cell anergy and deletion. Research into how self-reactive T cells are tolerized in LNs has focused largely on DCs. Depending on their functional status, antigen presentation by DCs can indeed lead to different forms of T cell tolerance (Steinman et al., 2003; Helft et al., 2010). Recently, however, LN-resident radio-resistant cells, the LN stromal cells (LNSCs), have been suggested to contribute to peripheral T cell tolerance. These cells can be discriminated based on their lack of CD45 expression and the differential expression of podoplanin (gp38) and PECAM (CD31). Fibroblastic reticular cells (FRCs, gp38⁺CD31⁻) produce chemokines such as CCL19 and CCL21, thereby providing a scaffold on which the CC-chemokine receptor 7 (CCR7)⁺ T cells and DCs can migrate and establish contact (Turley et al., 2010). In LNs, blood endothelial cells (BECs, gp38⁻CD31⁺) lining the high endothelial venules are crucial for lymphocyte entry (Mueller and Germain, 2009). Afferent lymphatic endothelial cells (LECs, gp38⁺CD31⁺) promote DC entry (Johnson et al., 2006; Acton et al., 2012), as well as antigen delivery (Sixt et al., 2005; Roozendaal et al., 2009), into LNs, whereas efferent LECs regulate T cell egress from LNs (Cyster and Schwab, 2012). The function of so-called double-negative (DN) stromal cells (gp38⁻CD31⁻) remains unknown. For many years, LNSCs were thought to only play an architectural role in LN construction and homeostasis. More recently, however, studies have identified LNSCs as active players in modulating adaptive immune responses (Swartz and Lund, 2012). In vitro, DC adhesion to LECs leads to decreased levels of co-stimulatory molecules by DCs (Podgrabinska et al., 2009). Furthermore, FRCs inhibit the proliferation of newly activated T cells through a NOS2-dependent mechanism, but also indirectly affect T cell proliferation by suppressing DC functions (Khan et al., 2011; Lukacs-Kornek et al., 2011; Siegert et al., 2011). In addition, FRCs can suppress acute T cell proliferation both in vitro and in vivo (Siegert et al., 2011). Other studies have convincingly demonstrated a role for LNSCs in maintaining peripheral CD8⁺ T cell tolerance via direct presentation of self-antigens to self-reactive CD8⁺ T cells. Unlike DCs, which acquire antigens and subsequently cross-present self-peptides to CD8⁺ T cells in the draining LNs, LNSCs ectopically express and present PTAs (peripheral tissue antigens) to CD8⁺ T cells, and consequently induce clonal deletion of self-reactive CD8⁺ T cells (Lee et al., 2007; Nichols et al., 2007; Gardner et al., 2008; Magnusson et al., 2008; Yip et al., 2009; Cohen et al., 2010; Fletcher et al., 2010). In addition, we have recently shown that tumor-associated LECs can scavenge tumor antigens and cross-present them to cognate CD8⁺ T cells, driving their dysfunctional activation (Lund et al., 2012). The lack of expression of co-stimulatory molecules such as CD80/86, and high PD-L1 expression levels at the surface of LECs (Fletcher et al., 2010; Tewalt et al., 2012), were proposed as the major mechanisms by which these cells induce deletional CD8⁺ T cell tolerance.While accumulating evidence suggests that direct antigen presentation by LNSCs promotes CD8⁺ T cell deletion, it is unknown whether LNSCs can similarly contribute to CD4⁺ T cell tolerance. As previously described, FRCs, BECs, and LECs express MHCII under virally induced inflammatory conditions or IFN-γ treatment (Malhotra et al., 2012; Ng et al., 2012). However, little is known about the regulation of MHCII expression by LNSCs.Here, we show that endogenous MHCII expression by LNSCs is controlled by the IFN-γ–inducible promoter IV (pIV) of class II transactivator (CIITA). Due to basal pIV activity, LNSCs express low levels of MHCII upon steady state and up-regulate these molecules when exposed to IFN-γ. Unexpectedly, in addition to low endogenous basal expression, the majority of MHCII molecules detected at LEC, BEC, and FRC surface were acquired from DCs. Furthermore, antigen-presenting DCs transfer antigenic peptide–MHCII (pMHCII) complexes to LNSCs, in a process dependent on both cell–cell contact and DC-derived exosomes. Importantly, acquired pMHCII complexes were presented by LECs, BECs, and FRCs to CD4⁺ T cells and promoted cognate CD4⁺ T cell dysfunction by impairing their survival and response to further restimulation. These data suggest that LNSCs serve more diverse roles than previously thought in regulating CD4⁺ T cell immunity.     

Myocardial injury after COVID-19 infection and vaccination. Two sides of the same coin or different?

The International Journal of Cardiovascular Imaging -     

Wounded by violence. Can a KISS (Kids, Injuries, and Street Smarts) make it better?

Last year, Tyrone Sinkler, 16, and Ian Moore, his 17-year-old buddy, were gunned down in the hallway of their New York City school by a disgruntled classmate. For many EMTs and paramedics, this tragedy would have just added to the helplessness we feel when we go on calls in which children kill children. But for some New York City EMS (NYC*EMS) personnel, this incidence added fuel to their fire of determination to prevent such violence. Through a program called KISS (Kids, Injuries and Street Smarts), which coincidentally was poised to begin about the same time as the Sinkler and Moore tragedy, NYC*EMS personnel strive to reduce traumatic injuries to adolescents.