Steady State Dendritic Cells Present Parenchymal Self-Antigen and Contribute to, but Are Not Essential for, Tolerization of Naive and Th1 Effector CD4 Cells

Abstract

Bone marrow-derived APC are critical for both priming effector/memory T cell responses to pathogens and inducing peripheral tolerance in self-reactive T cells. In particular, dendritic cells (DC) can acquire peripheral self-Ags under steady state conditions and are thought to present them to cognate T cells in a default tolerogenic manner, whereas exposure to pathogen-associated inflammatory mediators during the acquisition of pathogen-derived Ags appears to reprogram DCs to prime effector and memory T cell function. Recent studies have confirmed the critical role of DCs in priming CD8 cell effector responses to certain pathogens, although the necessity of steady state DCs in programming T cell tolerance to peripheral self-Ags has not been directly tested. In the current study, the role of steady state DCs in programming self-reactive CD4 cell peripheral tolerance was assessed by combining the CD11c-diphtheria toxin receptor transgenic system, in which DC can be depleted via treatment with diphtheria toxin, with a TCR-transgenic adoptive transfer system in which either naive or Th1 effector CD4 cells are induced to undergo tolerization after exposure to cognate parenchymally derived self-Ag. Although steady state DCs present parenchymal self-Ag and contribute to the tolerization of cognate naive and Th1 effector CD4 cells, they are not essential, indicating the involvement of a non-DC tolerogenic APC population(s). Tolerogenic APCs, however, do not require the cooperation of CD4+CD25+ regulatory T cells. Similarly, DC were required for maximal priming of naive CD4 cells to vaccinia viral-Ag, but priming could still occur in the absence of DC.

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

“…Our data contrast with the two previous reports implicating anergy induction as a key tolerogenic mechanism for memory or effector CD4 1 T cells. One report indicates that resting, but not activated, B cells inactivate memory CD4 1 T cells through anergy induction [23], whereas the second report shows that DC may be dispensable and that the key mechanism is induction of anergy [29]. Comparison of these data with ours suggests that B cells or other non-DC tolerogenic APC induce anergy in memory CD4 1 T cells, whereas DC appear to induce both deletion and unresponsiveness.…”

“…40: 2016Immunol. -2025 Immunomodulation , whereas the second report shows that DC may be dispensable and that the key mechanism is induction of anergy [29]. Comparison of these data with ours suggests that B cells or other non-DC tolerogenic APC induce anergy in memory CD4 1 T cells, whereas DC appear to induce both deletion and unresponsiveness.…”

FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer

“…Tissue-specific or tumor antigens may be taken up by resting DCs and cross-presented, resulting in the tolerization of T cells (13)(14)(15). Furthermore, others have reported that pDCs residing in tumor may deliver poor or tolerogenic signals to T cells (16)(17)(18)(19)(20).…”

Probing in vivo dendritic cell functions by conditional cell ablation

“…Viruses cDC requirement for LCMV, 35 HSV-1, 36 VSV, 37 influenza, 38 CTL response cDC independence of anti-VSV B and CD4 T-cell response 36,39 Bacteria cDC requirement for anti-Listeria CTL response 11,40 cDC requirement for efficient Mycobacterium tuberculosis CD4 T-cell response 41 cDC requirement for anti-Salmonella response 42,43 cDC independence of UPEC clearance 44 Parasites cDC requirement for anti-Plasmodium 11 and anti-Leishmania response 45,46 Prions cDC requirement for intestinal Scrapie agent neuroinvasion 47 Miscellaneous Tolerance cDC role in Ig complex-mediated priming and tolerization 48,49 cDC independence of peripheral CD4 T-cell tolerization 50 NK responses cDC requirement for NK cell activation by IL-15 trans-presentation 25 NKT responses cDC requirement for glycolipid presentation 51,52 CTL responses cDC requirement for efficient CTL memory generation 27 Respiratory tract cDC requirement for asthma and experimental allergic rhinitis 18,53 Tumor studies cDC requirement for antitumor immunity 52 DC functions by conditional cell ablation A Sapoznikov and S Jung subpopulations and generally provided by non-hematopoietic cells, including stromal and follicular dendritic cells; 58 and (2) the chemokine macrophage migration inhibitory factor (MIF) that controls mature B-and tumor cell survival through triggering of the CD74-CD44 receptor complex. [59][60][61] 70 on pDC.…”