Immuno Test 2 (Part 1) Flashcards
Properties of Cytokines
- Act locally in PARACRINE or AUTOCRINE fashion
- Usually NOT in bloodstream, only IN SICK PEOPLE
- Have small number of HIGH-AFFINITY CELL SURFACE RECEPTORS to produce changes in pattern of RNA and protein synthesis
- At at VERY LOW CONCENTRATIONS (10^-10- 10^-12)
- Utilize JAK/STAT of the RAS-MAP kinase pathways
Cytokine Signaling
- Bind to homodimeric or heterodimeric receptors, CONSTITUTIVELY BOUND TO JAKS
- JAKS activated by CONFORMATION CHANGE in the receptors that allows TRANS and/ or AUTO-PHOSPHORYLATION of the two bound JAKS
- These in turn PHOSPHORYLATE THE CYTOKINE RECEPTORS
- Stat protein bind the phosphorylated receptor, allowing the JAKS to PHOSPHORYLATE the STATS
- Stats form DIMERS AND TRANSLOCATE and accumulate in the NUCLEUS, where they REGULATE GENE EXPRESSION
Cytokines
Critical Role in:
1) INFLAMMATORY REACTIONS (pro and anti)
2) LINKING INNATE and ADAPTIVE IMMUNITY
3) Activation of T CELLS (Th1/ Th2)
4) Activation of B CELLS and AB PRODUCTION (Isotope Switching)
5) Control of HEMATOPOIESIS
Pleitrophy (Cytokines are pleiotropic)
Exhibit multiple effects on growth and differentiation of a variety of cell types
- Ex: IL-4
Properties of Individual CYTOKINES
1) REDUNDANCY
- There is overlapping and redundancy between cytokines
- IL-2, IL-4, IL-5 —> Proliferation
2) SYNERGY
- Cytokines can Synergies the effects of each other
- IL-4 + IL-5 —> Induces class switch to IgE
3) ANTAGONISM
- Cytokines can antagonize the effects of each other
- IL-4 + IFN-gamma —> Block class switch to IgE induced by IL-4
Cytokine Cascade
- A cascade is where one cytokine includes the production of another
- Th cells (IFN-gamma)–> Macrophage (IL-12) —> Th cells (IL-2, IFN-gamma, TNF-beta, etc..)
TNF
- Produced by Macrophages and T cells
Endothelial cells: activation (inflammation, coagulation) Neutrophils: Activation Hypothalamus: Fever Liver: Synthesis of Acute Phase Proteins Muscle, Fat: Catabolism (Cachexja) Manny cell types: Apoptosis
IL-1
- Produced by Macrophages, Endothelial cells, T lymph, Fibroblasts, Platelets
Endothelial cells: Activation (Inflammation, coagulation)
Hypothalamus: Fever
Liver: Synthesis of Acute Phase Proteins
Chemokines
- Produced by Macrophages, Endothelial cells, T Lympho, Fibroblasts, Platelets
Leukocytes: Chemotaxis, Activation
IL-12
- Produced by Macrophages and Dendritic Cells
NK and T cells: IFN-gamma synthesis, increased cytolytic activity
T cells: Th1 differentiation
IFN-gamma
- Produced by NK cells, and T Lympho
Activation of Macrophages
Stimulation of some Antibody Responses
IFN- alpha and IFN-beta
- Produced:
IFN-alpha: Macrophages
IFN-beta: Fibroblasts
All cells: antiviral state, increased class I MHC expression Activates NK Cells
IL-10
- Produced by Macrophages, and T Cells (Th2
Macrophages: Inhibition of IL-12 production, reduced expression of costimulators and Class II MHC molecules
IL-6
Produced by Macrophages, Endothelial cells, and T cells
Liver: Synthesis of Acute Phase Proteins
B cells: Proliferation of Antibody-producing cells
IL-15
- Produced by Macrophages, others
NK Cells: Proliferation
T Cells: Proliferation
IL-18
- Produced by Macrophages
NK Cell and T Cells: IFN-gamma synthesis
Cytokines and Actue Inflammation
- Some cytokines are Pro-Inflammatory
- Cytokines respond to infection, immune responses, inflammation, and trauma
Pro-Inflammatory Cytokines:
-IL-1
-TNF-alpha
-IL-6
-IL-8
-IL-11
-IL-12
-IL-15
-IL-18
PRO-INFLAMMATORY CYTOKINES have NF-KAPPA B DEPENDENT Transcription!!!!!!!
Anti-Inflammatory Cytokines:
- IL-10
- TGF-beta
- Control inflammation and promote healing
ANTI-INFLAMMATORY CYTOKINES are NF-KAPPA B INDEPENDENT!!!!!!!
Pro-Inflammaotry Cytokines
- TNF, IL1, and IL-6 are the major Pro-Inflammatory Cytokines
TNF= first most important!!!
Pro-Inflammatory Cytokines
- Work LOCALLY but promote SYSTEMIC INFLAMMATION
- TNF (need less) and IL-1 (need more) are PROTOTYPIC Pro-Inflammatory Cytokines
- They produce fever, systemic inflammation, shock, and death
- Reducing the activities of TNF and IL-1 is accomplished by NEUTRALIZING ANTIBODIES, SOLUBLE RECEPTORS, and RECEPTOR ANTAGONIST
- Blocking TNF and IL-1 has been high SUCCESSFUL in patients with RHEUMATOID ARTHRITIS, INFLAMMATORY BOWL DISEASE, or GRAFT-vs-HOST DISEASE
- Blocking TNF and IL-1 HAS NOT BEEN SUCCESSFUL in humans with SEPSIS!!!!
Effects of TNF/ IL-1
- Have Local and Systemic Effects
Systemic: (SYSTEMIC MANIFESTATIONS OF INFLAMMATION)
- Fever
- Leukocytosis
- Incr Acute Phase proteins
- Decr Appetite
- Incr Sleep
Local:
1) Vascular Endothelium: (INFLAMMATION!!!!)
- Incr Expression of Leukocyte ADHESION MOLECULES
- Production of IL-1, cheekiness
- Incr Procoagulant and Decr Anticoagulant activity
2) Leokocytes: (INFLAMMATION!!!!)
- Activation
- Production of Cytokines
3) Fibroblasts: (REPAIR!!!!)
- Proliferation
- Incr Collagen Synthesis
TNF
- Primarily produced by Macrophages and Monocytes (TNF-alpha), T Lympho (TNF-beta), Neutrophils, and NK Cells
- ENDOTOXIN (LPS) is the MOST POTENT INDUCER OF TNF!!!!!!
- Interacts with ENDOTHELIAL CELLS to INDUCE ICAM-1, VCAM-1, and E-SELECTIN, permitting the egrets of granulocytes into inflammatory loci
- TNF is PRIMARY MEDIATORY OF SEPTIC SHOCK!!!!!!!!!
- Potent ACTIVATOR OF NEUTROPHILS, Mediating Adherence, Chemotaxis, Degranulation, and the Respiratory Burst
- Binds to TNF RECEPTOR I (TNFR p75!!!!!!!) anf TNF REceptor II (TNFR p55!!!!!!!)
- TNF Induces ANTITUMOR IMMUNITY through direct CYTOTOXIC Effects (APOPTOSIS) on Cancerous Cells
IL-1
- Primarily produced by Macrophages and Monocytes but is also produced in less amounts by other cells such as Neutrophils, Endothelial cells, Keratinocytes, and other cells
- Interacts with CNS to produce FEVER, LETHARGY, SLEEP, and ANOREXIA
- Stimulates ICAM-1, VCAM-1, and E-Selectin on Endothelial cells, but “SECOND IN LINE” after TNF
- Only IL-1 INDUCES production of IL-2 by, and PROLIFERATION of, CD4 T Lymphocytes
- IL-1 stimulates synthesis of ACUTE-PHASE PROTEINS (“SECOND IN LINE” after IL-6)
- Can be NEUTRALIZED by natural IL-1 Receptor Antagonist, IL-1ra!!!!!!!!!!
IL-6
- Primarily produced by Mononuclear Phagocytic Cells but also by other cells like T and B Lympho, Fibroblasts, Endothelial cells, Keratinocytes, Hepatocytes, and Bone Marrow Cells
- IL-6 MOST IMPORTANT Inducer of ACUTE-PHASE PROTEINS
- IL-6 shares Several ACTIVITIES with IL-1, including INDUCTION OF PYREXIA (fever) but IL-1 is more important for induction of fever
- IL-6 STIMULATES differentiation of B Lympho into MATURE PLASMA CELLS producing Abs
- IL-6 has a PRIMARY ROLE in Th17 IMMUNE REGULATION!!!!!!!!!!1
IL-8
- Produced by Macrophages in response to an Inflammatory Stimulus
- Onset of Inflammation, MAST CELLS release IL-8 from their granules
- A CHEMOTACTIC FACTOR NEUTROPHILS, but not Monocytes
- Involved in NEUTROPHIL ACTIVATION
IL-12
- PRIMARILY derived from DENDRITIC CELLS and MACROPHAGES which produce much more IL-12 than B Cells, PMNs, and Mast cells
- HETERODIMER that consists of IL-12p40 and IL-12p35 subunits!!!!!!!!!!!!!!!
- CELL-MEDIATED IMMUNITY via Activation of Th1 cells
- Stimulates IFN-gamma production and activates and induces Proliferation, Cytotoxicity, and Cytokine production of NK CELLS
- SYNERGIZES with IL-8 also know as IFN-gamma INDUCING FACTOR, to stimulate IFN-gamma release
IL-15
- Produced by Mononuclear Phagocytic Cells although Epithelial cells, Fibroblasts are additional sources
- MOST IMPORTANT activity of IL-15 is ACTIVATION of NK CELLS!!!!!!!
- Similar to IL-2, IL-15 is a T CELL GROWTH FACTOR!!!!!!!!
- Chemotactic for T LYMPHOCYTES!!!
- IMPORTANT for the survival of CD8 MEMORY CELLS!!!
IFN-gamma
- Primarily made by Th1 CELLS and NK CELLS
- Critical in many INNATE and ADAPTIVE IMMUNITY Aspects
- Most Important CYTOKINE for CELL-MEDIATED IMMUNITY by orchestrating an Immune Response to INTRACELLULAR PATHOGENS!!!!!!!!!!!!
- MAJOR ACTIVATOR of Intracellular killing of pathogens by Macrophages, by STIMULATING PHAGOCYTOSIS, SECRETION, RESPIRATORY BURST, and NITRIC OXIDE production
Il-12 and IFN-gamam SYNGERY
- Th1 cells produce IFN-gamma that activate Macrophages
- Macrophages produce IL-12 which activates Th1 Cells
IFN-gamma
STIMULATES:
1) Killing by NK Cells and NEUTROPHILS
2) Expression of MHC I and II
3) Ag PRESENTATION BY APCs
4) CYTOKINE PRODUCTION by APCs
5) EXPRESSION of ICAM-1
INHIBITS:
1) ALLERGIC RESPONSES by Suppressing many IL-4 mediated effects!!!!!!!!! (NO IgE!!!)
- Has modest ANTIVIRAL ACTIVITY unlike Type I Interferons IFN-alpha and IFN-beta
Anti-Inflammatory Cytokines
- IL-10, IL-1 Receptor Antagonist (IL-1ra), and TGF-beta
- Inhibit Pro-Inflammatory response
- Act in concert with Other Inhibitors to REGULATE THE HUMAN IMMUNE SYSTEM
- Physiological ROLE IN INFLAMMATION and Pathologic role in SYSTEMIC INFLAMMATORY stare are INCREASINGLY RECOGNIZED
IL-10
- Important Immuno-regulatory cytokine
- PRIMARILY INDUCED by Macrophages, B cells, and T Regulatory Cells
- INHIBITS production of:
- IL-1 beta
- IL-6
- IL-8
- IL-12
- TNF-alpha by Mononuclear Phagocytes
INHIBITS:
1) Expression of CLASS II MHC by APCs!!!!!!!!!!
2) Expression of co-stimulatory molecules the CD80 and CD86 by APCs
3) Production of IFN-gamma and TNF-beta by Th1 Lympho (CELL-MEDIATED IMMUNITY)
4) Production of IL-4 and IL-5 by Th2 (ANTIBODY MEDIATED IMMUNITY)
- Controls TOLERANCE to Environmental Allergens!!!
TGF-beta
- Most PLEIOTROPIC of the CYTOKINES!!! (Stimulatory and Inhibitory effects on numerous cells)
- PRIMARILY PRODUCED by Macrophages and T Regulatory Cells
- STIMULATES Fibrosis promoting WOUND HEALING and SCAR formation
- INHIBITS PROLIFERATION B Cells and CD8+ T Lympho
- INHIBITS Macrophage and NK Cells
- INDUCES APOPTOSIS in B cells and CD8+ T Lympho
- REGULATES the differentiation of Th17 Lympho
M1/ M2 Macrophages
M1: (Classical)
- Induced by TLR-ligands and IFN-gamma
- Produce: IL-1, IL-12, IL-23 —> INFLAMAMTION
- Produce: ROS, NO, and Lysosomal enzymes —> PHAGOCYTOSIS AND KILLING OF BACTERIA AND FUNGI
M2: (Alternative)
- Induced by IL-13 and IL-4
- Produce IL-10 and TGF-beta —-> ANTIINGLAMMATORY EFFECTS
- Produce Proline Polyamines, TGF-bets —-> WOUND REPAIR, FIBROSIS
IL-2
Action:
- Survival, Proliferation, and Differentiation of Effector and Regulatory T Cells
Resources:
- CD4+ and CD8+ T cells
IL-4
Action:
- B Cell Switching to IgE
Source:
- CD4+ T cells, Mast Cells
IL-5
Action:
- Activation of Eosinophils
Source:
- CD4+ T Cells, Mast Cells
IFN-gamma
Action:
- Activation of Macrophages
Source:
- CD4+ and CD*+ T cells, NK Cells
IL-17
Action:
- Stimulation of Actute Inflammation
Source:
- CD4+ T Cells
TGF- Beta
Action:
- Inhibition of T cells activation; Differentiation of Regulatory T cells
Source: CD4+ T cells, many other cells
Cytokine Network in Adaptive Immunity with Th0 cells and APC
1) APC produces IL-12 then becomes Th1 (Makes IL-1 and IFN-gamma) —> CTL
2) Low levels of IL-4 then becomes Th2 (Makes IL-4) —> Plasma Cell
3) APC produces IL-1, IL-6 becomes Th17 (Makes IL-17A, IL-17F, IL-22, and IL21)
- Has IL-23R
4) APC produces TGF-beta, IL-2 becomes Treg (Makes IL-10)
- Has IL-2Ralpha
Differentiation of Different T-helper subsets is controlled at the Transcriptional Level
1) T-BET = TH1 cells!!!!
2) GATA-3 = TH2 CELLS!!!!
3) RORgammaT = TH17
4) FOXP3 = T REGULATORY CELL
TH1
Cytokine:
- IFN-gamma
Immune Reaction:
- Macrophage Activation; IgG production
Host Defense:
- INTRACLLULAR MICROBES
Role in Diseases:
- Autoimmune diseases; tissue damage associated with CHRONIC INFECTIONS
TH2
Cytokine:
- IL-4
- IL-5
- IL-13
Immune Reaction:
- Mast Cell, Eosinophil activation
- IgE production
- Alternative Macrophage Activation
Host Defense:
- HELMINTHIC PARASITES
Role in Diseases:
- Allergic Diseases
TH17
Cytokine:
- IL-17A
- IL-17F
- IL-22
Immune Reactions:
- Neutrophilic Monocytic Inflamamtion
Host Defense:
- EXTRACELLULAR BACTERIA, FUNGI
Role in Disease:
- Autoimmune and Inflammatory Diseases
IL-2 Controls Proliferation of T Cells
- Naive T cells express low-affinity IL-2 receptors (IL-2R) complex, made up of the Beta and Gamma C chains
- On ACTIVATION by antigen recognition and costimulation, the cells produce IL-2 and express the alpha chain of the IL-2R forming the HIGH-AFFINITY IL-2 receptor
- Binding of IL-2 to its receptor INITIATES PROLIFERATION of the T cells that recognized the antigen
Proliferation of T Cells
- IL-2 STIMULATES PROLIFERATION of T Cells
- IL-2 STIMULATES EXPRESSION OF IL-2R which is not present on Naive T cells, but is SYNTHESIZED within a few hours after activation
- IL-2 acts only on cells which express HIGH_AFFINITY IL-2R
- IL-2R INCREASES the number of IL-2R on the cells!!!!!
- If Ag is cleared, the IL-2R NUMBER DECLINES!!!!
- TGF-beta BLOCKS IL-2 INDUCED Proliferation is a KEY mechanism of control of T cells proliferation
Cytokines Control the Th1/ Th2 Differentaition
- IL-12 INDUCES differentiation of Th0 cells into TH1 cells!!!
- TH1 cells characteristically SECRETE IL-2, IFN-gamma, and TNF-beta (lymphotoxin) and promote CELL-MEDIATED IMMUNITY!!!!!!!!!!!!!
- IL-4 induces differentiation of TH2 cells, which SECRETE IL-4, IL-5, IL-6, IL-10, and IL-23
- TH2 cells ACTIVATE B LYMPHOCYTES resulting in up regulation of ANTIBODIES (HUMORAL IMMUNITY!!!!!)
- TH1 and TH2 cells have MUTUALLY INHIBITORY EFFECTS on the reciprocal phenotype
- IFN-gamma Inhibits TH2 cell proliferation!!!!!!!!
- IL-10/ IL-14 INHIBIT TH1 cell proliferation!!!!!
TH1/ TH2 Response
- DC ARE CRITICAL in diviing differentiatoin towards Th1 or TH2 phenotype
- Subpopulations of specialized DCs for the STIMULATION of EITHER Th1 of Th2 population
- IL-12 INDUCES TH1 cells!!!!!!!
- IL-4 INDUCES TH2 cells!!!!!
- IL-12 and IFN-gamma SYNERGIZE in Selective differentiation of TH1 cells
- IFN-gamma/ IL-12, and IL-4 MEDIATE the mutual antagonism of Th1 and Th2
Role of TH1 in Host Defense
- IL-12 CONTROLS Th1 differentiation
- TH1 PRODUCES IFN-gamma which activates phagocytes to KILL PHAGOCYTIZE MICROBES (CLASSICAL PATHWAY M1)
- TH1 cells STIMULATE the production of ANTIBODIES with promote Phagocytosis of microbes
- AB = IgG!!!!!!!!!!!!!!!!!
Th1 in Infections with Intracellular Microbes
1) Wild type (IFN-gamma+, IL-12+) can control infection of tuberculosis
2) IL-12 KNOCKOUT (IFN-gamma+, IL-12-) can NOT control tuberculosis infection and die because no TH1 ADAPTIVE IMMUNITY
3) IFN-gamma KO MICE (IFN-gamma-, IL-12+) die EARLY because Macrophages are not activated properly in the absence of IFN-gamma!!!
TH2 Cells in Host Defense
- Th2 cells produce IL-4 which STIMULATES PRODUCTION of IgE ANTIBODY!!!!!!!
- IgE participates in the ACTIVATION OF MAST CELLS by protein Antigens
- IgE binds to HELMINTHS!!!
- Produce IL-5, which ACTIVATES EOSINOPHILS!!!!!!!
- Eosinophils DESTROY THE HELMINTHS!
- IL-4 induces ALTERNATIVE activation of Macrophages (M2)
Cytokines Control Ab Isotype Switch
IgM:
- Complement Activation
IgG (and subclasses): —> IFN-gamma!!!!!
- Fc receptor dependent phagocyte repsonses
- Complement activation
- Neonatal Immunity (placental transfer)
IgE: —> IL-4!!!!!!!!
- Immunity against Helminths
- Mast Cell degranulation (Immediate Hypersensitivity)
IgA: —> TGF-beta, BAFF
- Mucosal Immunity
- Transport of IgA through Epithelia
- HELPER T cells: CD40L, and Cytolines help produce these ANTIBODIES!!!!!!!!
Maturation of MHC-Restricted T cells
1) WEAK RECOGNITION of Class II MHC + peptide = POSITIVE SELECTION (CD4+ Mature T Cell) -> CD4+/ CD8-
2) WEAK RECOGNITION of Class I MHC + peptide = POSITIVE SELECTION (CD8+ Mature T Cell) -> CD8+/ CD4-
3) NO RECOGNITION of MHC + peptide = FAILURE OF POSITIVE SELECTION (Death by Neglect)!!!!!!
4) STRONG RECOGNITION OF either Class I or II MHC + peptide = NEGATIVE SELECTION!!!!!!
- Ag- independent maturation of T cells occurs in the THYMUS. Only stem cells are from Bone Marrow
- T cell starts out at CD4+/ CD8+ Immature T cells!!!!!!!
T Lyphocytes
- Only 1 in 10^6 have specific TCR can recognize a given pathogen
- TCR recognize peptides within Class I and II MHC
- CD4 or CD8 co-receptors binds to CLASS II and CLASS I
- Naice T cells are ACTIVATED by APCs (Dendritic Cells) and Proliferate
- PATHOGEN-SPECIFIC T Cells are MADE by CLONAL EXPANSION “On Demand”!!!!!!!!!
Activation of T Cells Occurs in LN
1) Antigen uptake by Langerhan (Immature dendritic cells) cells
2) Langerhan cell leaves the skin and enter the Lymphatic System
3) Langerhan cells enter the LN to become dendritic cells expressing B7!!!!!!!
4) B7-Positive Dendritic cells Stimulate Naive T cells!!!!!
- Langerhan’s cells are immature DCs do not express B7!!!!!
Lymph Node: Morphology
- Ag is delivered for T cells by activated Dendritic Cells via Lymphatic Vessels
- DC loaded with Ag move into T cell Zone located in PARAFOLLICULAR CORTEX!!!!!! aka INNER CORTEX
- Naive T cells enter the LN via blood stream
Functional Role of CD4 and CD8
- CD4 T Cells = Class II MHC
- CD8 T Cells = Class I MHC
- CD4 and CD8 co-receptors function to concentrate the ATTENTION of T helper cells and CTLs on the PROPER MHC
- CD4 and CD8 help to clip onto CLASS II or CLASS I MHC
* CD4 and CD8 are SIGNALING CO-Receptors!!!!**
T Cells are MHC Restricted
- T cells initiated by singling CASCADE
- The Alpha and Beta chains have very SHORT INTERCELLULAR DOMAINS
- Signaling is mediated OTHER PROTEINs comprising TCR Complex!!!
- CD3 PROTEINS (gamma, delta, epsilon and zeta) have CYTOPLASMIC TAIL that is long enough to SIGNAL
** TO ACTIVATE T CELLs we need ALL: TCR, CD3, and CD4 or CD8
Co-Stimulation: CD80- CD28
- T Cells must receive a co-stimulatory Signal
- With co-stimualtion about 100 fold fewer of clustered TCRs are NEEDED FOR ACTIVATION
- B7 PROETINS (CD80 and CD86) which expressed on APC, are co-stimualtor molecules
- B7 molecules plugging into CD28 RECEPTOR expressed on T Cells
- Thus, Co-stimulation POTENTIATES the activating single from TCR-Ag-MHC!!!!
*** Proliferation and differentiation of T cells specific for bacterial protein!!!!
Co-Stimulatory Signal
1) Resting APC (No Costimulators) = ANERGY (No response or functional inactivation)
2) Activated APC (Costimulators expressed) = T Cell Proliferation!!!
- Newly activated T cells produce IL-2 and thus stimulate their own proliferation
- Activated T cells doubled every 6 hours!!
Il-2 is T Cell Growth Factor
- Activation is completed, the T helper cell and APC are separated
- APC foes on to activate OTHER T CELLS
- T CELL Proliferates in order to INCREASE THE NUMBER OF Ag- specific cells
- Proliferation driven by IL-2 “T cell growth factor”
- Naive T cells DO NOT HAVE IL-2 receptor (IL-2R) expressed on surface
- ACTIVATED T CELLS produce large amount of IL-2 and EXPRESSED IL-2R
IL-2 and IL-2R in T Cell Proliferation
** Secretion of IL-2 causes the IL-2R to change from low affinity to high affinity!!!!!!!
- Expression of IL-2Raplha chain
- Formation of high-affinity IL-2Ralpha,beta,gamma COMPLEX!!!
Re-Stimulation of Activated T Cell
- FIRST TIME ACTIVATED T CELLs and proliferate and PRODUCE ONLY IL-2 (not committed to Th1 or Th2 yet)
- These cells are re-stimultaed by APC (Second Contact with APC) and begin to SECRETE OTHER CYTOKINES( Committed Th1 to Th2)
- (IFN-gamma +TNF) or (IL-4, IL-5, IL-10) - Activated T cells “go home” after T CELL HOMING!!!
- Homing is COMING TO THE TISSUE form which the Ag-loaded Dendritic cell has arrived to the LN
- TISSUE MACROPHAGES are involved in re-stimulation of the arrived T cells!!!
