The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a mouse model with defective mitochondrial function in CD4(+) T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation, and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward proinflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD(+) levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify strategies for intervention in mitochondrial-related diseases.

HDAC6 is a tubulin deacetylase involved in many cellular functions related to cytoskeleton dynamics, including cell migration and autophagy. In addition, HDAC6 affects antigen-dependent CD4 + T cell activation. In this study, we show that HDAC6 contributes to the cytotoxic function of CD8 + T cells. Immunization studies revealed defective cytotoxic activity in vivo in the absence of HDAC6. Adoptive transfer of wild-type or Hdac6

Objective. To define and characterize the progression of the spontaneous autoimmune disease that develops in mice in the absence of the leukocyte adhesion receptor P-selectin glycoprotein ligand 1 (PSGL-1).Methods. Skin-resident immune cells from PSGL-1-deficient mice and C57BL/6 control mice of different ages were isolated and analyzed by flow cytometry. Biochemical parameters were analyzed in mouse serum and urine, and the presence of serum autoantibodies was investigated. Skin and internal organs were extracted, and their structure was analyzed histologically.Results. Skin-resident innate and adaptive immune cells from PSGL-1 ؊/؊ mice had a proinflammatory phenotype with an imbalanced T effector cell:Treg cell ratio. Sera from PSGL-1 ؊/؊ mice had circulating autoantibodies commonly detected in connective tissuerelated human autoimmune diseases. Biochemical and histologic analysis of skin and internal organs revealed skin fibrosis and structural and functional abnormalities in the lungs and kidneys. Furthermore, PSGL-1 ؊/؊ mice exhibited vascular alterations, showing loss of dermal vessels, small vessel medial layer remodeling in the lungs and kidneys, and ischemic processes in the kidney that promote renal infarcts.Conclusion. Our study demonstrates that immune system overactivation due to PSGL-1 deficiency triggers an autoimmune syndrome with characteristics similar to systemic sclerosis, including skin fibrosis, vascular alterations, and systemic organ involvement. These results suggest that PSGL-1 expression contributes to the maintenance of the homeostasis of the immune system and could act as a barrier for autoimmunity in mice.

P-selectin glycoprotein ligand-1 (PSGL-1), a leukocyte adhesion receptor that interacts with selectins, induces a tolerogenic programme in bone marrow-derived dendritic cells (DCs), which in turn promotes the generation of T regulatory (Treg) lymphocytes. In the present study, we have used a mouse model of dextran sulphate sodium (DSS)-induced colitis and studied the characteristics of the inflammatory cell infiltrate in the lamina propria (LP), mesenteric lymph nodes (mLNs) and Peyer's patches (PPs) to assess the possible role of PSGL-1 in the modulation of the enteric immune response. We have found that untreated PSGL-1-deficient mice showed an altered proportion of innate and adaptive immune cells in mLNs and PPs as well as an activated phenotype of macrophages and DCs in the colonic LP that mainly produced pro-inflammatory cytokines. Administration of an anti-PSGL-1 antibody also reduced the total numbers of macrophages, DCs and B cells in the colonic LP, and induced a lower expression of MHC-II by DCs and macrophages. After DSS treatment, PSGL-1(-/-) mice developed colitis earlier and with higher severity than wild-type (WT) mice. Accordingly, the colonic LP of these animals showed an enhanced number of Th1 and Th17 lymphocytes, with enhanced synthesis of IL-1α, IL-6 and IL-22, and increased activation of LP macrophages. Together, our data indicate that PSGL-1 has a relevant homeostatic role in the gut-associated lymphoid tissue under steady-state conditions, and that this adhesion receptor is able to down-regulate the inflammatory phenomenon in DSS-induced colitis.

Viral infections involve specific stress exposure that can influence the quality and average lifespan of an organism. The immune system acts through virus clearance from the organism. Many aspects of immune cells accounting for this response are still under study. Here, we review recent aspects of the molecular mechanisms involved in the delivery of the lethal hit by Cytotoxic T lymphocytes.