T Cell Proliferation Induced by Autologous Non-T Cells Is a Response to Apoptotic Cells Processed by Dendritic Cells

Abstract

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.

Aberrant Phenotype and Function of Myeloid Dendritic Cells in Systemic Lupus Erythematosus

“…Furthermore, Koller et al (54) used irradiated DCs for their mixed-lymphocyte reaction studies, while we used nonirradiated DCs. Irradiated DCs can undergo apoptosis (90) and posttranslational modifications of proteins during apoptosis can potentially modify T cell activation and proliferation (90). Our results do confirm a previous observation that CD83 expression on lupus DCs is not up-regulated after maturation stimuli (91), are supported by similar ex vivo findings in DCs isolated from peripheral blood and, as mentioned, are reminiscent of what has been reported in lupus animal models (85).…”

Monocyte‐derived dendritic cells can induce autoreactive CD4+ T cells showing myeloid lineage directed reactivity in healthy individuals

“…Although profound cytokine production by autoDC-reactive CD4 + T cells was observed, this did not coincide with overt cytotoxicity against autoDCs. In contrast to the In agreement with previous studies on autologous mixed lymphocyte reaction, autoDC reactivity was mainly mediated by CD4 + T cells [14][15][16]29]. We demonstrated that the initial autoDCinduced proliferation of most CD8…”

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

“…How-ever, it is known that antibodies with specificity for RNA binding and DNA binding proteins and at least dsDNA can occur during infections (71,72). There is also a recent report that normal human T lymphocytes have a strong reactivity against apoptotic material presented by dendritic cells, explaining the syngeneic mixed leukocyte reaction (73). Consequently, an autoimmune repertoire resembling that seen in systemic autoimmune diseases such as SLE may exist within the normal immune system.…”