Self-reactive T cells are present in the mature immune repertoire as demonstrated by T cell proliferation induced by autologous non-T cells in the autologous mixed lymphocyte reaction. This reaction generates regulatory T cells in vitro and may reflect immune regulatory pathways in vivo, but the antigenic peptides recognized remain uncharacterized. We revisited this issue in light of the importance of apoptosis in immune regulation. We found that apoptosis among peripheral blood non-T stimulator cells is associated with augmented induction of autologous T cell proliferation. Our data show that caspase activity in the non-T stimulator population is essential for induction of autologous T cell proliferation, suggesting that cellular components in the non-T cell fraction are enzymatically modified, most likely by effector caspases, and have a direct or indirect effect on autoreactive T cell activation. Furthermore, exposure of macrophage-derived dendritic cells to apoptotic non-T cells augments autologous T cell proliferation, and blockade of αvβ5 integrin, but not αvβ3, inhibits the capacity of irradiated non-T cells or dendritic cells to stimulate autologous T cell proliferation. These experiments, using an entirely autologous system, suggest the interpretation that autoreactive T cells may recognize self-Ags modified through the actions of caspases and presented to T cells by dendritic cells. Induction of an in vivo autologous mixed lymphocyte reaction by caspase-modified self-Ags present in apoptotic cells may represent a mechanism to maintain peripheral immune tolerance.
Tumor infiltrating lymphocytes (TIL) display activation markers and their presence is often associated with a favorable outcome. The role of tumor antigens in T cell recruitment into tumors is unclear. In an attempt to address this issue, we purified lymphocytes from breast tumor or nontumor, mammary tissue from patients, and normal mammary tissue from healthy individuals. In all groups, including healthy individuals, the majority of cells displayed an effector/memory (CD45RA lo /CD27 1/2 ) phenotype and quite surprisingly the early and transient activation marker CD69, thus, questioning the tumor antigen specificity of TIL. Because the human repertoire is diverse, the T cells found in the tumors could recognize both self/tumor and environmental antigens through cross-reactivity. To test this hypothesis, we used two anti-male HY monospecific TCR transgenic mouse models. We found an infiltration of HY negative tumors by the CD4 1 and CD8 1 monoclonal T cells after priming with HY positive cells in the periphery. Thus, the presence of activated effector/memory T lymphocytes in tumors can be independent of reactivity against tumor antigens. These results suggest that to find activated effector T cells in a tissue does not always mean that a specific immune response is taking place. ' 2005 Wiley-Liss, Inc.Key words: human; rodent; tumor immunity; T cells; cell trafficking Tumor infiltrating lymphocytes (TIL) are found in different types of tumors and their presence has been correlated with a better outcome in patients with melanoma 1,2 and carcinoma of the kidney, 3 esophagus, 4 stomach, colon, 5,6 ovaries 7 and breast. 8,9 TIL are mostly T cells and a number of these have been demonstrated to be specific for tumor antigens. [10][11][12][13][14][15][16][17] Together with the discovery of tumor antigens, this led to the hypothesis that these TIL were actively fighting the tumor. 10,18 However, the proportion of tumor-specific vs. nonspecific T cells found in tumors is not known and the role of antigen in the intratumor accumulation of T cells is unclear. The intratumor T cells specific for tumor antigens are often viewed as the effector arm of the immunesurveillance model. This model is still challenged by 2 observations: (i) the increased incidence of tumors observed in immunodeficient patients is low for most common tumors, 19 (while it is high only for tumors that are virus-induced, such as HPV (Human papilloma virus)-induced skin and cervical cancers or EBV (Epstein-Barr virus)-related lymphoma) and (ii) the outcome of most common cancers in immunodeficient patients is comparable to that seen in immunocompetent patients. Moreover, some authors 20 argue against the increased tumor frequency observed by others 21 in immunodeficient mice, although these results have been disputed. 20 Taken together, these observations made in humans and mice call into question the fundamental role of the immune response to control tumor growth beside its antiviral activity.As breast cancer does not seem to be virally induced, the co...
BackgroundMutations in the CLN3 gene lead to so far an incurable juvenile-onset neuronal ceroid lipofuscinosis (JNCL) or Batten disease that starts at the age of 4–6 years with a progressive retinopathy leading to blindness. Motor disturbances, epilepsy and dementia manifest during several following years. Most JNCL patients carry the same 1.02-kb deletion in the CLN3 gene, encoding an unusual transmembrane protein, CLN3 or battenin.ResultsBased on data of genome-wide expression profiling in CLN3 patients with different rate of the disease progression [Mol. Med., 2011, 17: 1253–1261] and our bioinformatic analysis of battenin protein-protein interactions in neurons we propose that CLN3 can function as a molecular chaperone for some plasma membrane proteins, being crucially important for their correct folding in endoplasmic reticulum. Changes in spatial structure of these membrane proteins lead to transactivation of the located nearby receptors. Particularly, CLN3 interacts with a subunit of Na/K ATPase ATP1A1 which changes its conformation and activates the adjacent epidermal growth factor receptor (EGFR). As a result, a large amount of erroneously activated EGFR generates MAPK signal cascades (ERK1/ERK2, JNKs and p38) from cell surface eventually causing neurons’ death.ConclusionsMolecular mechanism of the juvenile form of Batten disease (JNCL), which is based on the excessive activation of signaling cascades in a time of the radical increase of neuronal membranes’ area in the growing brain, have been proposed and substantiated. The primary cause of this phenomenon is the defective function of the CLN3 protein that could not act properly as molecular chaperone for some plasma membrane proteins in the endoplasmic reticulum. The incorrect three-dimensional structure of at least one such protein, ATP1A1, leads to unregulated spontaneous and repetitive activation of the SRC kinase that transactivates EGFR with the subsequent uncontrolled launch of various MAPK cascades. Possible ways of treatment of patients with JNCL have been suggested.ReviewersThis article was reviewed by Konstantinos Lefkimmiatis, Eugene Koonin and Vladimir Poroikov.
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