1. “Negative” Regulation of the Adaptive Immune Response
Chander Raman, Ph.D.
February 2018

2. Regulation of immune response by:
Crossregulation between Th subsets
Treg cells
Breg Cells
Tolerogenic dendritic cells
Myeloid DC (conventional DC)
Plasmacytoid DC
Myeloid derived suppressor cells (MDSC)
Cytokines
Exosomes
PD1/PDL (1/2)

3. Regulation of immune response by:
Crossregulation between Th subsets
Treg cells
Breg Cells
Tolerogenic dendritic cells
Myeloid DC (conventional DC)
Plasmacytoid DC
Myeloid derived suppressor cells (MDSC)
Cytokines
Exosomes
PD1/PDL (1/2)

4. Cross-regulation of different CD4 subsets
Induced Treg (iTreg)
Deenick and Tangye. Nature Sept. 2007

5. Regulation of immune response by:
Crossregulation between Th subsets
Treg cells
Breg Cells
Tolerogenic dendritic cells
Myeloid DC (conventional DC)
Plasmacytoid DC
Myeloid derived suppressor cells (MDSC)
Cytokines
Exosomes
PD1/PDL (1/2)

6. Inhibition (attenuation)
A model for the relationship between developmental outcome and TCR affinity for self-peptide–MHC.
A model for the relationship between developmental outcome and TCR affinity for self-peptide–MHC. Cells with TCR that have a low affinity for self die by neglect. Those with an intermediate affinity are positively selected. High-affinity self-reactive clones can die via clonal deletion, and the threshold between positive and negative selection is hypothesized to be steep. Regulatory T cells (Treg) (yellow) have more highly self-reactive TCRs than most conventional T cells (purple). Some Tregs may have very highly self-reactive TCRs and are rescued from deletion via cytokine signaling or by virtue of having a second TCR (dotted line).
Signal Strength
Co-stimulation
Inhibition (attenuation)
Xing Y , Hogquist K A Cold Spring Harb Perspect Biol 2012;4:a006957
©2012 by Cold Spring Harbor Laboratory Press

8. Models for thymic TReg cell development
Hsieh and Lio. Nat. Rev. Immunol.12:157 (2012)

9. TReg cell activation and differentiation.
Liston and Gray. Nat. Rev. Immunol. 14:154 (2014)

10. Wood, Bushell & Hester, Nat. Rev. Immunol. 12, 417-430 (2012)

11. Life cycle of regulatory and conventional CD4+ T cells.
Rosenblum, Way and Abbas. Nat. Immunol. Epub Dec. 21, 2015

12. Predicted model for the relationship between resting, effector and memory TReg cells.
Rosenblum, Way and Abbas. Nat. Immunol. Epub Dec. 21, 2015

13. Molecular mediators of tissue-resident TReg cell homeostasis.
Liston and Gray. Nat. Rev. Immunol. 14:154 (2014)

14. Mechanisms of reciprocal antagonism between Treg and Teff cell populations.
Roychoudhuri, Eil, Restifo. Current Opinion in Immunology, Volume 33, 2015, 101–111

16. Regulation of immune response by:
Crossregulation between Th subsets
Treg cells
Breg Cells
Tolerogenic dendritic cells
Myeloid DC (conventional DC)
Plasmacytoid DC
Myeloid derived suppressor cells (MDSC)
Cytokines
Exosomes
PD1/PDL (1/2)

18. Functional Properties of Breg Cells
Elizabeth C. Rosser, Claudia Mauri
Volume 42, Issue 4, 2015, 607–612
Figure 1. Functional Properties of Breg CellsThrough the production of IL-10, TGF-β, and IL-35, Breg cells can suppress the differentiation of pro-inflammatory lymphocytes, such as tumor necrosis factor α (TNF-α)-producing monocytes, IL-12-producing dendritic ...

19. Annual Reviews

20. Annual Reviews

21. Regulation of immune response by:
Crossregulation between Th subsets
Treg cells
Breg Cells
Tolerogenic dendritic cells
Myeloid DC (conventional DC)
Plasmacytoid DC
Myeloid derived suppressor cells (MDSC)
Cytokines
Exosomes
PD1/PDL (1/2)

22. Myeloid DC in T-cell Immunity and Regulation
Adrian E. Morelli & Angus W. Thomson
Nature Reviews Immunology 7, (August 2007)

23. Differentiation of DC VIP – vasoactive intestinal peptie
TSLP – Thymic stromal lymphoprotein
HGF - hepatocyte
Raker, Domogalla and Steinbrink Frontiers in Immunology, Nov 2015

24. Plasmacytoid DC
Guéry and Hugues, Frontiers in Immunology, March 6, 2013

25. Regulation of immune response by:
Crossregulation between Th subsets
Treg cells
Breg Cells
Tolerogenic dendritic cells
Myeloid DC (conventional DC)
Plasmacytoid DC
Myeloid derived suppressor cells (MDSC)
Cytokines
Exosomes
PD1/PDL (1/2)

26. The origin of MDSCs. Dmitry I. Gabrilovich & Srinivas Nagaraj
Nature Reviews Immunology 9, (March 2009)

27. Suppressive mechanisms mediated by different subsets of MDSCs.
Dmitry I. Gabrilovich & Srinivas Nagaraj
Nature Reviews Immunology 9, (March 2009)

28. Tumor‑infiltrated myeloid cells contribute to the immunosuppressive network in tumors
Kusmartsev, S. and Vieweg, J. (2009) Enhancing the efficacy of cancer vaccines in
urologic oncology: new directions
Nat. Rev. Urol. doi: /nrurol

29. Regulation of immune response by:
Crossregulation between Th subsets
Treg cells
Breg Cells
Tolerogenic dendritic cells
Myeloid DC (conventional DC)
Plasmacytoid DC
Myeloid derived suppressor cells (MDSC)
Cytokines
Exosomes
PD1/PDL (1/2)

30. IL-2

31. IL-2: The currency of Treg and Teff cell population dynamics.
Roychoudhuri, Eil, Restifo. Current Opinion in Immunology, Volume 33, 2015, 101–111

32. Klatzmann and Abbas Nat. Rev. Immunol. 15:283, 2015

33. TGF-β

35. Cytokines of Type 2 Immunity

36. Wynn, T.A. Nat. Rev. Immunol. 15:271, 2015

37. The yin and yang of type 2 immunity.
Wynn, T.A. Nat. Rev. Immunol. 15:271, 2015

38. Macrophage subsets regulate inflammation and wound healing.
Peter J. Murray & Thomas A. Wynn
Nature Reviews Immunology 11, (November 2011

39. Regulation of immune response by:
Crossregulation between Th subsets
Treg cells
Breg Cells
Tolerogenic dendritic cells
Myeloid DC (conventional DC)
Plasmacytoid DC
Myeloid derived suppressor cells (MDSC)
Cytokines
Exosomes
PD1/PDL (1/2)

40. Exosomes
• Exosomes are extracellular vesicles (<100 nm in size) that are derived from the endocytic compartment of the cell.
• They are generated by the reverse budding of the limiting membrane of late endosomes, which then become multivesicular bodies (MVBs) containing intraluminal vesicles (ILVs).
• Exosomes are released into the extracellular milieu by fusion of the peripheral membrane of MVBs with the plasma membrane.
• Exosomes have a protein and lipid composition that is different from that of other types of extracellular vesicle released from the plasma membrane by shedding from living cells (that is, ectosomes and particles) or by blebbing from cells undergoing apoptosis (that is, apoptotic cell blebs).
Robbins and Morelli Nat.Rev. Immunol. 14:195, 2014

41. Th1 suppression by Treg derived Exosomes
PD1/PDL (1/2)
Chatila and Willaims
Immunity 

42. Regulation of immune response by:
Crossregulation between Th subsets
Treg cells
Breg Cells
Tolerogenic dendritic cells
Myeloid DC (conventional DC)
Plasmacytoid DC
Myeloid derived suppressor cells (MDSC)
Cytokines
Exosomes
PD1/PDL (1/2)

43. PD1/PDL (1/2)

44. Arlene H. Sharpe
 & Kristen E. Pauken Nature Reviews Immunology, 13 November 2017