1) The document discusses a presentation given by Kazuyoshi Takeda at the 8th India Probiotic Symposium on the topic of enhancement of natural killer (NK) cell activity by probiotics. 2) It provides background on NK cells and their role in immunity, and suggests that probiotics like Lactobacillus casei Shirota (LcS) may augment NK cell activity by interacting with macrophages and dendritic cells in the intestine and stimulating cytokine production. 3) A proposed mechanism involves LcS entering the body through M cells in the intestine, stimulating dendritic cells and macrophages to produce cytokines like IL-12 and IFN-γ that then activate NK cells, enhancing immunity

1. 2016.12.03
Kazuyoshi Takeda
Division of Cell Biology, Biomedical Research Center
and Department of Biofunctional Micribiota,
Graduate School of Medicine,
Juntendo University, Tokyo, Japan
8th INDIA PROBIOTIC SYMPOSIUM
“PROBITOTICS IN HEALTH-EMERGING OPPORTUNITIES”
Enhancement of Natural Killer Cell Activity
by Probiotics
Session 1: Probiotics in Allergy and Immunity

2. ＝ reactions to eliminate foreign material (non-self)
from the body (self) by lymphoid cells
→ rejection in organ transplantation
virus, bacteria, parasites
cancer cells ＝ crazy non-stop growing cells
out of control
The crazy marks are expressed on cell surface.
Immune cells attack cancer cells
basing on the recognition of these crazy marks.
Immunity ＝ mechanisms to avoid diseases
Not distinguish an enemy from a friend
How about cancer cell?
Cancer cells are originally derived from a self cell
≒ pathogens

3. rough recognition strictly recognize
one cell responses to many
（handy man）
one cell response to one
(
How much does it
cost for activation?
Improved by habits and/or diet Activated by vaccination
instable
(sensitive to many stimulants)
stable
so so
cheep
quick
skillful
high
slow
not at the first encounter
learn and remember
quick response at the 2nd encounter
at the first encounter
quick response
Natural Immue Res. Acquired Immune Res.
Immunity
Speed of start up
Recognition
of enemy
＝ Natural immunity+ Acquired immunity
when memory is kept,
never get same disease
resistant to diseases,
but not completely
not completely prevent/cure completely prevent/cure

4. eat help kill make
antibodies
NK cellMacrophage B cell
4 8
T cell
kill
Front line Headquarters
Front line provides the information of the enemy.
At the second invasion of same enemy, headquarters
promptly attack with more effective ways based on
the information provided by front line at first encounter.
1：natural immunity 2：acquired immunity
quick, cheap, and so so slow, expensive, and skillful

5. HELP
information
natural immunity acquired immunity
4 8
4 8
4 8
foreign
bodies
foreign
bodies
attackattack
foreign
bodies
attack
information
Dendritic cells(DC)

6. information
dendritic cells (DC)
HELP
information
natural immunity acquire immunity
4 8
4 8
4 8
attack
foreign
body
foreign
body
foreign
body
prompt and forceful attack
by activated CD8T and B cells
information
dendritic cells (DC)
prompt and forceful attack
by activated CD8T and B cells
information
dendritic cells (DC)

7. Cooperation of two kinds of immunity in self-defense
Bacteria Virus Tumor cells

8. NK cell: natural killer cell：born killer cell
one subset of lymphocytes killing the
cells that do not belong to self even at the
first encounter
What is NK cell？
NK cell activity (killing activity)
= how many tumor cells NK cells can kill in 4 h (%)
100806040200
NK cell activity（％）
Numberofpersons
NK cell activity (killing activity) is various individually.

9. The patients genetically impaired in NK cell, but not T and B
cells, suffer from severe infections with herpes virus.
What does happen in the human who has
no NK cells or low NK cell activity ?
Elderly humans with low NK cell activity exhibit a higher
mortality rate due to infectious diseases compared with
their counterparts with high NK cell activity.
Epidemiological study revealed that the population with low
NK cell activity has a significantly higher risk of cancer than
the population with intermediate or high NK cell activity.

10. Decrease in NK cell number and/or activity
↓
Higher risk of cancer development and
infectious diseases
↓
Augmentation of NK cell activity
possibly reduces the risk of cancer
development and infectious diseases
↓
How augment NK cell activity in daily life?

11. Supplementation of live beneficial bacteria
promotes health and reduces the risk of various diseases.
Probiotics are live microorganisms which,
when administered in adequate amounts,
confer a health benefit on the host.
(FAO/WHO 2001)
yoghurt, fermented foods, some mushrooms, etc
Improvement of the dietary habits
take good foods for health and reduce ill foods
Yakult：Fermented milk drink containing
Live Lactobacillus casei Shirota (LcS)
Do probiotics augment NK cell activity?

12. Augmentation of NK cell activity by LcS intake

13. %
%
(E/T =20)
LcS more effectively augments NK cell activity
in the people who need NK cell activation.
NK cell activation by LcS is more effective
in the persons who have lower NK cell activity

14. To activate NK cells by the oral intake of LcS,
LcS must go into the body through epithelium.
Such experiments do not sufficiently explain
how LcS augment NK cell activity in vivo.

15. M. Takahashi, et al.
LcS
Lactic acid bacteria phagocytized by M
cells
LcS

16. M cell
Intestine
NK cell
Macrophage
and/or
Dendritic
cell
T cell
CBLcSCB
Enteric
microbiota
Commensal
bacteria
Regulation
Mucosal Immunity
Intestinal Immunity
LcS
LcS enter into the body through M cell at
intestine

17. Correlation between augmentation of cytotoxic activity
and IL-12 production in LcS-induced NK cell activation
PBMC were co-cultured with freeze-dried LcS in
vitro

18. M cell
Intestine
Cancer
Pathogens
LcS LcS
IL-12
activation
activation
by contact
IFN-g
NK cell
Macrophage
and/or
Dendritic
cell
Possible mechanisms of LcS-induced NK cell activation
activation
Probiotics augments NK cell
activity via the enhancement of
immune responses in intestine
1. Probiotics possibly enter into a body at intestine.
2. DC and Mf recognize probiotics and
produce NK cell activating
cytokines
(e.g. IL-12, IFN-g).
3. NK cells are activated and would prevent diseases.

19. 4 8
4 8
4 8
LcS
LcS
LcS
LcS
LcS
LcS
LcS
LcS
LcS

20. Juntendo University, School of Medicine
Department of Immunology
K. Okumura
F. Nagao
Yalult Central Institute for Microbiological Research
M. Nanno
T. Suzuki
K. Shida
S. -I. Shimada
Y. Matsuoka
Y. Yamaoka
Takane Hospital
H. Takane
Acknowledgements