Classical DC (cDC) are required for efficient protective T-cell immunity. Moreover, recent data indicate that cDC also play a critical role in mediating homeostatic proliferation and maintenance of peripheral Treg. Here, we corroborate these findings by defining CD80/ CD86 costimulation as an essential molecular component required for the cDC-Treg interactions. In contrast to earlier reports, the reduced Treg compartment of mice lacking cDC or selective CD80/86 expression on cDC, as such, did not render the respective animals prone to systemic lymphocyte hyperactivation or autoimmunity. Rather, we provide evidence that elevated immunoglobulin titers, as well as changes in T-cell subset prevalence and activation status are strictly associated with the nonmalignant myeloproliferative disorder triggered by the absence of cDC. IntroductionProductive T-cell activation requires, in addition to the TCR stimulus, a second signal provided by costimulatory molecules, the best characterized of which are CD80 (B7-1) and CD86 (B7-2). CD80 and CD86, which are expressed mainly on B cells, DC and medullary thymic epithelial cells (mTEC) [1], are the only known ligands of CD28 and CTLA-4 receptors on T cells. Functions of CD28 and CTLA-4 are distinct with CD28 promoting T-cell activation and CTLA-4-negative regulating T-cell responses.Peripheral self-tolerance and immune homeostasis are maintained, at least in part, by a delicate balance of T effector and Treg. CD25 1 CD41 Treg, which arise spontaneously as the so-called In vitro studies have revealed that BM culture-derived DC selected for high expression of CD86 are particularly effective in driving Treg proliferation [10] and that conversely DC isolated from CD80/86 double knockout mice poorly promote Treg division [4]. Moreover, emerging evidence supports a direct correlation between DC numbers and the proliferation rate of peripheral Treg. Thus, Fms-like tyrosine kinase 3 ligand (Flt3L) treatment, which results in the in vivo expansion of classical DC (cDC) [11] leads to a concomitant increase in peripheral Treg [12,13]. Furthermore, it was recently demonstrated that the conditional ablation of cDC from otherwise intact animals results in reduced numbers and impaired homeostatic proliferation of peripheral Treg [13].Here, we readdressed the role of cDC in the maintenance of peripheral Treg focusing on the role of CD80/86 costimulation. Using constitutive and conditional cDC ablation strategies, we established that peripheral Treg maintenance critically depends on the presence of cDC expressing CD80/86. Surprisingly however and defying earlier notions [13,14], the reduction of Treg in animals lacking cDC as such was not inherently associated with lymphocyte activation. Rather than resulting from a tolerance failure, the autoinflammatory signatures reported for cDCdeficient mice are thus a consequence of the nonmalignant myeloproliferative disorder these animals develop.

Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages (MDMs). However, whether TRMs and MDMs have functional distinction under differing pathologies is not understood. Here, we show a significant portion of macrophages that accumulated during pancreatitis and pancreatic cancer were expanded from TRMs. We further established that pancreas TRMs have a distinct extracellular matrix remodeling phenotype that was critical for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and animal death, due to impaired acinar cell survival and recovery. In pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.

No abstract

No abstract