Properties and functions of effector T cells Flashcards
What is the only cell type that can stop inflammatory actions of Th17?
Treg
Activation/priming of naive CD8+ T cells on encounter with antigen
- antigen specific signal
- co stimulatory signal
- cytokine signal
The 3rd signal for Tc cell activation comes from _____ in the form of ___
APC; IL-12
- IL-12 directs immune responses toward CD8 Tc cell responses (adaptive cellular immune responses)
Proteins in granules of cytotoxic T cells
Perforin, granzymes, granulysin
Perforin
Aids in delivering contents of granules into the cytoplasm of target cell
Granzymes
Serine proteases, which activate apoptosis once in the cytoplasm of the target cell
Granulysin
Has antimicrobial actions and can induce apoptosis
Cytokines
IFN-gamma, LT- alpha, TNF-alpha
Cytotoxic effector molecules
Fas ligand
Delivery of cytotoxins is aimed ___
Directly at the target cell, upon specific antigen recognition by cytotoxic T cell
Cytotoxic recognition process
Collision and nonspecific adhesion –> specific recognition redistributes cytoskeleton and cytoplasmic components of T cell –> release of lytic granules at site of contact
Life cycle of a Tc cell
Antigen recognition –> activation –> clonal expansion –> differentiation into memory CD8+ T cell or effector CD8+ T cell = killing of infected target cells or macrophage activation
*differentiation occurs in the peripheral tissues, while everything else occurs in lymphoid organs
Cytotoxic T cells are _____ and _____ of target cells
Selective; serial killers
- CTL recognizes virus-infected cell –> CTL programs target cell to die –> CTL moves to another target cell –> first target cell dies
Cytotoxic T cells kill their targets by ___
Inducing apoptosis
- apoptotic products will be taken up by macrophages or DC
Thymus regulatory tolerance
T cell specific for self antigen recognized in thymus becomes a natural regulatory T cell (aka central Tregs)
Peripheral regulatory tolerance
T cell specific for self or commensal microbiota antigen recognized in persence of TGF-beta becomes an induced regulatory T cell (aka peripheral Tregs)
Cytokines produced by Treg cells
IL-10 and TGF-beta
- inhibit other self-reactive T cells (located in the periphery)
What part of thymic selection eliminates autoreactive T cells?
- negative selection
- T regs get rid of T cells that escape thymic elimination
General properties of regulatory T cells
FOXP3+CD4+CD25+Tregs
Suppress the proliferation and IL-2 production of naive cells
- both CD4+ and CD8+ cells could be suppressed
Effector mechanisms of regulatory T cells
- Surface molecules: constitutive expression of CTLA-4 (CD152)
- Cytokines: IL-10, TGF-beta (release of cytokines suppresses activation of all cells)
- Cytotoxins, perforin, gransyme A, Fas-FasL
CTLA-4
Molecule that inhibits activation
Anything that ____ or _____ has a stronger binding effect
Regulates; inhibits
Foxp3
Max transcriptional factor that directs development of T regs
Regulatory T cells suppression mechanisms
Cell to cell contact dependent and soluble factor (IL-10 or TGF-beta) dependent suppression
CTLA-4 binds to _____, sending dendritic cell into apoptosis, or an inactive state
CD80/86
IL-10
- potent immunomodulatory cytokine
- anti inflammatory
- down regulates production of Th-1 type cytokines
- decreases expression of MHC 2 and co stimulatory molecules on DCs (tolerogenic state)
- regulates activation/function of mast cells
- regulates cytokine production by eosinophils
- directly suppresses T cell proliferation
Migration of DCs
- Steady state: migrate everyday, contributes to homeostasis
- Pathogen induced: only happens during infection
Triadic function of TGF-beta
- Sword: paralyzes cell activation/differentiation to suppress immune response
- Wand: converts naive T cells into iTregs and Th17 to aid in their combat against inflammation and infection
- Shield: protect and maintain Tregs against apoptosis and destabilization when surrounded by inflammation and consistent stimulation
Cytotoxins
Perforin, Gransyme A
Th17 cells
- physiologic role in immunity by conferring protective function against microbial pathogens
- represent pro-inflammatory subset, which in excess contributes to autoimmunity and tissue damage
- various subsets of Th17 cells with distinct function and pathogenic capacity
Non pathogenic subset
Incapable of promoting autoimmune inflammation and might act anti-inflammatory
Highly pathogenic Th17
From naive precursor cells that occur independently of TGF-beta signaling in the presence of IL-23, IL-6 and IL-1B
Tregs vs Th17
- both pathways are reciprocally interconnected, requiring a balance between both cell types = influence over outcome of immune response
- shared requirement of TGF-B provides phenotypic and functional plasticity in both populations = differentiated cells to “re” differentiate
- Th17 = pro-inflammatory, which can turn into autoimmune when in excess, while Tregs have antagonistic effect, that when in failure also leads to autoimmune diseases
TH17/Treg balance provides a basis for understanding the immunological mechanisms that ______ and _______
Induce/regulate autoimmunity; chronic inflammation
Therapeutic approaches
Targeting molecules influencing the Th17/Tregs axis
Mechanisms that contribute to immunological self-tolerance
- negative selection in the bone marrow and thymus
- expression of tissue-specific proteins in the thymus
- no lymphocyte access to some tissues
- suppression of autoimmune responses by regulatory T cells
- induction of anergy in autoreactive B and T cells
Anergy
Absence of co stimulatory signal, naive T cells that have received the first signal become anergic and die by apoptosis
Immunological tolerance
Non responsiveness of the lymphocyte population to the specific antigen self (self tolerance) or non-self
Peripheral tolerance
Antigen recognition in the absence of the co stimulatory signal
Co stimulatory signal and specific signal
Activates T cell
Specific signal alone
T cell becomes anergic
Co stimulatory signal
No effect on T cell
Immunologically privileged sites
- brain
- eye
- testis
- uterus (fetus)
- hamster cheek pouch
Tolerogen
When an antigen induces tolerance
The most important form of tolerance is ____
Non reactivity to self antigens
Mechanisms of central tolerance
- negative selection in the thymus
- autoimmune regulator (AIRE)
Mechanisms of peripheral tolerance
- absence of co stimulatory signal
- immunologically privileged sites (immunological ignorance)
- regulatory T cells
