Autophagy plays multifaceted roles in both the innate and adaptive immune system. In innate immunity, autophagy aids in the recognition of pathogens by pattern recognition receptors like TLRs, NLRs, and RLRs. It also facilitates the handling and destruction of intracellular bacteria by phagocytosis and lysosomal fusion. Autophagy regulates the production of cytokines as well. In adaptive immunity, autophagy contributes to antigen presentation on MHC class I and II molecules and is important for the homeostasis and functions of lymphocytes like T cells and B cells. However, the precise mechanisms in some cases require further clarification.

1. .

3. Outline
Introduction to autophagy
Autophagy in innate immunity
Autophagy in adaptive immunity
Conclusion
References

4. Autophagy
• An intracellular homeostatic mechanism
important for the degradation of waste
components from the cytoplasm in acidic
lysosomal compartments.
• Targets: Range of pathogens with particular
emphasis on intracellular bacteria.

5. Types of Autophagy :

6. Immunology
Autophagy pathway:

7. Autophagy in immune system
Autophagy is most ancient of immune
defences.
Autophagy has now evolved multifacetted
role.
Autophagy has now become a bonafide
regulator of both innate and acquired
immune system.

8. Autophagy in innate immunity
Autophagy and pattern
recognition patterns.
Autophagy and bacteria
handling.
Autophagy and cytokines.

9. TLR4 is able to induce
autophagy in murine
macrophages following
stimulation with
lipopolysaccharide
(LPS). ( Shi CS, Kehrl JH.)
• LPS stimulation of
TLR4 was shown to
increase the clearance
of Mycobacterium
tuberculosis by
autophagy. (xu Y, Jagannath C,
Liu XD)
• TLR9 Front. Immunol., 25 June 2014
Autophagy and PRRs

10. Autophagy can also play a role in facilitating
recognition of PAMPS by TLRs
Autophagy was able to
deliver viral ligands to
TLR7 in plasmacytoid
dendritic cells (pDCs)
following vesicular
stomatitis virus and
Sendai virus infection
resulting in type I
interferon production (lee et
al)
Front. Immunol., 25 June 2014

11. Autophagy and NLRs
• Activation of the NLRs in mice
leads to recruitment of
Atg16L1 at the plasma
membrane to the site entry of
invading Shigella flexneri and
Listeria monocytogenes,
resulting in their sequestration
in autophagosomes and
subsequent destruction. Travassos
LH, Carneiro LA, Ramjeet M et al.)
Annual Reviews

12. Annual Reviews
In humans, the treatment of
DCs with the NOD2 ligand
muramyldipeptide (MDP) has
been shown to induce autophagy
(Cooney R, Baker J, Brain O et al.)

13. Autophagy and NLRS
• NLRs induce autophagy
• Absence of NOD2 signalling resulted in increased
bacterial burden, attributed to poor autophagy
induction. (Lapaquette P, Bringer M, Darfeuille-Michaud A.)

14. NLRs can also inhibit autophagy
• NLRP4 can inhibit
autophagy through its
ability to bind and inhibit
the action of Beclin 1.
Front. Immunol., 21 November 2013

15. Autophagy and RLRs
• Acts downstream of virus-sensing pathways
mediated by RLRs.
• Treatment with the polyinosine-polycytidylic acid,
acting through the RLR is able to induce autophagy
in melanoma cells resulting in autophagy-dependent
cell death.(Tormo D, Checinska A, Alonso-Curbela D et al)

16. Negative regulation of RLRs by autophagy
• Atg5-deficient murine macrophages have increased
RLR signalling mediated by enhanced reactive
oxygen species production owing to an increase in
mitochondrial volume.(Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS,
Iwasaki A)

17. Autophagy and bacteria handling
1. Uptake of cytosolic bacteria:
• Autophagy leads to uptake of cytosolic bacteria
mediated by a central adaptor protein called p62
• Listeria monocytogenes persists in cell due to
inhibition of autophagy by Listeriolysin,
Phospolipase C and actin polymerization protein A
(Yoshikawa Y, Ogawa M, Hain T et al)

18. 2. Removal of vacuolar bacteria
Autophagy facilitates the fusion of BCG-
containing vacuoles with lysosomes to facilitate
mycobacterial killing (Birmingham L, Canadien V et al)
When infected with M. tuberculosis, mice with a
myeloid lineage-specific deletion of Atg5
exhibited enhanced mycobacterial burden
compared with wild-type controls, alongside
increased tissue necrosis and lung pathology. (Castillo
EF, Dekonenko A, Arko-Mensah J et al.)

19. 3.Bacteria induce autophagy
• Pseudomanas aeruginosa is able to induce
autophagy in the alveolar macrophages cell line
MH-S.(Yuan et al)
• Knockdown of beclin 1 with small interfering RNA
or treatment with the autophagy inhibitor 3-MA
resulted in a marked increase in bacterial load
whereas treatment with the autophagy inducer
Rapamycin improved bacterial clearance. (Watson RO,
Manzanillo PS, Cox JS)

20. NETs
• PMA-induced NETosis was found to be dependent
on autophagy and treatment of neutrophils with the
autophagy inhibitor wortmannin was able to exert
an inhibitory effect on NET formation.
• Pharmacological manipulation of autophagy could
induce or inhibit NET formation and mediate the
delivery of factors important for NET function (Itakura
A, McCarty OJT)

21. Autophagy and cytokines
• Interferon- γ ((Th1) cytokine ) is a potent
inducer of autophagy while the IL-4 and IL-
13(Th2 cytokines ) have been shown to have
inhibitory effect

22. Autyophagy and cytokines
• Role in the biogenesis and secretion of various
proinflammatory cytokines.
• Atg16L1-deficient macrophages exhibit
enhanced IL-1 β and IL-18 secretion following
stimulation with LPS.

23. Autophagy and cytokines
Production of multiple other cytokines is
enhanced in the absence of autophagy
Increases in IL-1α, IL-12, IL-17 and CXCL1
were all observed in Atg5fl/fl LysM-Cre+ mice
compared with wild-type controls in response
to M. tuberculosis infection.

24. • TNF-α and IL-6 secretion are also regulated by
autophagy;
• Inhibition of autophagy with 3-MA or knockdown of
beclin 1 and Atg7 promotes IL-1α, IL-1β and IL-23
secretion by macrophages and DCs and this in turn
augments innate secretion of IL-17, IFN-γ and IL-
22 by γδ T cells.(Peral de Castro C, Jones SA, Cheallaigh CN et al.)

25. Autophagy and cytokines

26. Autophagy and adaptive immunity
Autophagy and antigen presentation
• MHC Class I presentation
• MHC Class II presentatioin
Autophagy in T cells
Autophagy in B cells

27. Autophagy and antigen presentation
MHC Class I presentation
• Limited evidence exists that autophagy plays a
role in the conventional MHC class I pathway.
• No improvement in MHC class I presentation of a
viral epitope when it was conjugated to LC3, a
mechanism that was able to enhance the
presentation of MHC class II antigens.(Schmid D, Pypaert
M, Munz C)
• Multiple other studies have also failed to report a
requirement for autophagy in MHC class I
presentation.(Lee HK, Mattei LM, Steinberg BE et al.)

28. Autophagy and MHC Class I….
Inhibition of autophagy was found to decrease
MHC class I surface expression in B16 murine
melanoma cells and subsequent tumour cell
cytolysis by CD8+ T cells.(Li B, Lei Z, Lichty BD, et al)
 Autophagy has been implicated in an alternative
pathway of MHC class I presentation that exists in
DCs and macrophages, termed cross-presentation.

29. Autophagy and MHC class I Ag
presentation
.

30. Autophagy and antigen presentation
MHC Class II presentatioin
Prominent role of the lysosomal system in MHC
class II presentation have linked autophagy to this
form of antigen presentation.
Traditionally, MHC class II antigens were believed
to be sourced from the extracellular space following
phagocytosis by antigen-presenting cells.

31. MHC Class II …
• More than 50% of MIICs were observed to receive
input from autophagosomes.(Schmid D, Pypaert M, Munz C)
• Analysis of the human B lymphoblastoid cell line
showed that some MHC class II epitopes were
derived from intracellular sources and starvation-
induced autophagy could enhance the presentation
of intracellular antigens on MHC class II
molecules.(Dengjel J, Schoor O, Fischer R et al.)

32. MHC Class II…
Use of starvation and Rapamycin in macrophages
and DCs can also increase MHC class II
expression of a mycobacterial antigen following
phagocytosis of BCG (Gerland LM)
The secreted antigen, Ag85B, was found colocalized
with LC3+ autophagosomes suggesting that
autophagy may capture antigens following their
escape from the phagosome and deliver them to the
lysosome to prime CD4+ T cells.

33. MHC Class II…
• Conjugation of the influenza matrix protein 1 to
LC3 could also enhance the priming of antigen-
specific CD4+ T cells.
• Mice with a DC-specific deletion of Atg5 have
impaired CD4+ T-cell priming in response to
herpes simplex virus infection (Lee HK, Mattei LM, Steinberg
BE et al)

34. Autophagy in the immune system
Immunology
Volume 141, Issue 1

35. Autophagy and T cells
Autophagy is constitutively present in T cells (Gerland
LM et al)
T cell development and selection (Nedjic J, Aichinger M,
Emmerich)
T cell deletion in Atg5-/- leads to increased apoptosis
due to loss of organelle quality.(Parekh VV, Wu L, Boyd KL et al.)
Proliferation following activation by Ag(Wang X, Gao Y,
Tan J et al.)
Loss of ER homeostasis (Jia W, He Y)
Regulation of energy metabolism (Hubbard VM, Valdor R,
Patel B)
iNKT cell development(Parekh VV, Wu L, Boyd KL et al.)

37. Autophagy and B cells
B cell development (Miller BC, Zhao Z, Stephenson LM et al.)
B cell homeostasis (Mortensen M, Ferguson DJ, Edelmann M, Kessler B,
Morten KJ, Komatsu, Simon AK. et al)
Differentiation of B cells into Plasma cells (Pengo N,
Scolari M, Oliva L et al.)
Regulated Ig secretion

39. Conclusion
Autophagy is implicated in pathogen sensing, phagocytosis, the
removal of intracellular pathogens, and cytokine production.
Role of autophagy in MHC Class II well known but in Class I not
understood
Autophagy is essential for the homeostasis of lymphocytes
Role of autophagy in certain functions of immune system is
unclear and needs further work

40. References
• Autophagy in the immune system :Daniel J. Puleston1 and Anna Katharina Simon
• journal of immunology published by John Wiley & Sons Ltd, Immunology, 141, 1–8 :2013
• Autophagy and cytokines :James Harris Immunology Research Centre, School of
Biochemistry & Immunology, Trinity College Dublin, College Green, Dublin 2, Ireland
• Autophagy and Its Role in MHC-Mediated Antigen Presentation :Victoria L. Crotzer and
Janice S. Blum J Immunol 2009;
• Autophagy and pattern recognition receptors in innate immunity; Monica
Delgado,Sudha Singh,Sergio De Haro ,Sharon Master etal Immunological Reviews 2009 Vol.
227: 189–202
• TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate
immunity :Emma M. Creagh and Luke A.J. O’Neil TRENDS in Immunology Vol.27 No.8
• Autophagy and the Immune System: Petric Kuballa, Whitney M. Nolte, Adam B.
Castoreno, and Ramnik J. Xavier Annu. Rev. Immunol. 2012. 30:611–46
• Pattern recognition receptors and autophagy Ji Eun Oh and Heung Kyu Lee Front.
Immunol., 25 June 2014 | doi: 10.3389/fimmu.2014.00300