Diferenciação e funções de linfócitos T

Question 1

Que tipo de resposta imunológica deve ser induzida para eliminar…

Answer 1

…células tumorais?
…uma infeção viral?
…uma infeção bacteriana?
…parasitas intestinais?

When naive CD4+ T cells are activated in secondary lymphoid organs, they proliferate and differentiate into effector cells.

Some of the effectors (the Th1, Th2, and Th17 populations)
mostly exit the lymphoid organ and function to
eradicate microbes in peripheral tissues.

Other differentiated cells, called follicular helper T (Tfh)
cells, remain in the lymphoid organ and help B cells to produce potent antibodies.

Question 2

Características de linfócitos CD4+ auxiliares

Answer 2

A naive CD4+ T cell may differentiate into subsets that produce different cytokines that recruit and activate different cell types (referred to as target cells) and combat different types of infections in host defense. These subsets also are involved in various kinds of inflammatory diseases.

The table summarizes the major differences among Th1, Th2, Th17 and Tfh subsets of helper T cells. –> flashcards difs

Question 3

Comparação - Th1

Answer 3

Effector T cells
Th1

Defining cytokines
IFN-gamma

Principal target cells
Macrophages

Major immune reactions
Macrophage activation

Host defense
Intracellular pathogens

Role in disease
Autoimmunity, chronic inflammation

Question 4

Comparação - Th2

Answer 4

Effector T cells
Th2

Defining cytokines
IL-4, IL-5, IL-13

Principal target cells
Eosinophils

Major immune reactions
Eosinophil and mast cell activation; alternative macrophage activation

Host defense
Helminths

Role in disease
Allergy

Question 5

Comparação - Th17

Answer 5

Effector T cells
Th17

Defining cytokines
IL-17, IL-22

Principal target cells
Neutrophils

Major immune reactions
Neutrophil recruitment and activation

Host defense
Extracellular bacteria and fungi

Role in disease
Autoimmunity, inflammation

Question 6

Comparação - Tfh

Answer 6

Effector T cells
Tfh

Defining cytokines
IL-21 (and IFN-gamma or IL-4)

Principal target cells
B cells

Major immune reactions
Antibody production

Host defense
Extracellular pathogens

Role in disease
Autoimmunity (autoantibodies)

Question 7

Diferenciação de subsets de

células T CD4 auxiliares

Answer 7

DCs and other immune cells that respond to different types of microbes secrete cytokines that induce the development of antigen-activated CD4+ T cells into the following subsets:

-Th1: intracellular microbes
+DC -IL-12-> / +NK cell -IFNg->
Antigen-activated T cell with transcription factors: T-bet, STAT4, STAT1 –> Th1 cell

• Th2: Helminths + DC + mast cells, eosinophils -IL-4-> Antigen-activated T cell with transcription factors: GATA-3, STAT6 –> Th2 cell
• Th17: extracellular fungi, bacteria + DCs -IL-1, IL-6, IL-23, TGFb -> Antigen-activated T cell with transcription factors: RORgt, STAT3 –> Th17 cell

Question 8

Funções de células efetoras Th1

Answer 8

Th1 cells secrete IFN-γ, which acts on macrophages to increase phagocytosis and killing of microbes in phagolysosomes.

Th1 cells also produce TNF-alfa, which activates neutrophils and promotes inflammation (not shown).

Question 9

Ativação de macrófagos por células efetoras Th1

Answer 9

A, Macrophages are activated by CD40L-CD40 interactions and by IFN-γ expressed by Th1 cells and perform several functions that kill microbes,
stimulate inflammation, and enhance the antigen presenting capacity of the
cells.

B, The principal responses of
macrophages activated by the classical activation pathway, and their roles in T cell-mediated host defense, are listed:

Production of NO, increased lysosomal enzymes, ROS -> likking of microbes in phagolysosomes (effector function of macrophages)

Secretion of cytokines (TNF, IL-1, IL-12) and chemokines –> TNF, IL-1, chemokines: leukocyte recruitment (inflammation);
IL-12: Th1 differentiation, IFN-g production

Increased expression of B7 costimulators, MHC molecules: –> increased T cell activation (amplification of T cell response)

Macrophages are also activated during innate immune reactions and perform similar functions.

Question 10

Funções de células efetoras Th2

Answer 10

Th2 cytokines: IL-4, IL-5 and IL-13

Helminths or protein antigens–> APC –> naive CD4+ T cell

CD4+ T cells that differentiate into Th2 cells secrete IL-4, IL-5, and IL-13. IL-4 (and IL-13) act on B cells to stimulate production of antibodies that bind to mast cells and eosinophils, such as IgE.

Help for antibody production may be provided by Tfh cells that produce Th2 cytokines
and reside in lymphoid organs, and not by classical Th2 cells.

IL-5 activates eosinophils, a response that is important
for defense against helminthic infections.

IL-4 and IL-13 are involved in immunity at mucosal barriers, induce an alternative pathway of macrophage activation, and
inhibit classical Th1-mediated
macrophage activation.

Question 11

Funções de células efetoras Th17

Answer 11

Cytokines produced by Th17 cells (IL-17, IL-22) stimulate local production of chemokines that recruit neutrophils and other leukocytes, increase production of antimicrobial peptides (defensins), and promote epithelial barrier functions.

Question 12

Papel das células TFH (T auxiliares foliculares) na resposta imunológica

Answer 12

TFH cells interact directly with B cells and generate effector cytokines, such as IL-21 and IL-4, which induce B-cell proliferation and differentiation into antibodyproducing plasma cells.

+ regulates affinity maturation of germinal center B cells

Question 13

Via clássica e alternativa de ativação de macrófagos

Answer 13

Different stimuli activate tissue macrophages to develop into functionally distinct populations.

Classically activated macrophages are induced by microbial TLR-ligands and cytokines, particularly IFN-γ, and are microbicidal and
involved in potentially harmful inflammation. (ROS, NO lysosomal enzimes; IL-1, IL-12; IL-23)

Alternatively activated macrophages are induced by IL-4 and IL-13 produced by Th2 cells and other leukocytes and function to control inflammation and to promote tissue repair and fibrosis (

Question 14

Indução e fase efetora da resposta imunológica mediada por linfócitos T CD8+

Answer 14

CD8+ T cells recognize antigens presented by DCs in peripheral lymphoid organs and are stimulated to proliferate and differentiate into effector cells (cytotoxic T lymphocytes, CTLs) and
memory cells.

The CTLs migrate to tissues
at sites of infection, tumor growth, or graft rejection, where they recognize the antigen and respond by killing the cells where the
antigen is produced.

Question 15

Papel das células T auxiliares na diferenciação de linfócitos T CD8+

Answer 15

CD4+ helper T cells promote the development of CD8+ CTLs and memory cells by secreting cytokines that act

• directly on the CD8+ cells (A)
• or by activating APCs to become more effective at stimulating the differentiation of the CD8+ T cells, e.g., by increasing the expression of costimulators on the APCs (B). =APC LICENCING (?)

Question 16

“Licenciamento” das APC e ativação dos linfócitos CD8+

Answer 16

O “priming” das CD8 por APCs não licenciadas resulta em:

• falha na expressçao de moléculas anti-apoptóticas
• tempo de vida curto
• falha na diferenciação da função citotóxica
• falha no estabelecimento de memória imunitária

Fatores trancrição (diferenciação de CTLs): T-bet, Eomes

Question 17

Eventos para indução de lise das células alvo por CTLs

Answer 17

Antigen recognition and immune synapse formation –> granule exocytosis –> Detachment of CTL –> Target cell death

A CTL recognizes the antigen-expressing target cell and is
activated.

Activation results in the release of granule contents from the CTL into the target cell through the area of contact (the immunologic synapse).

Granule contents deliver a lethal hit to the target. The CTL may detach and kill other target cells.

The formation of conjugates between a CTL and its target and activation of the CTL also require interactions between accessory molecules (LFA-1, CD8) on the CTL and their specific ligands (ICAM-1 and class I MHC, respectively) on the target cell (not shown).

Question 18

Mecanismos utilizados pelas CTL para indução de apoptose das células alvo

Answer 18

CTLs kill target cells by two main mechanisms.

A, Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes are delivered into the cytoplasm of the target cells by a perforin-dependent mechanism, and they induce apoptosis.

B, FasL is expressed on activated CTLs, engages Fas
on the surface of target cells, and induces apoptosis.

Question 19

Conceitos chave

Answer 19

• T cell responses are initiated by signals that are generated by TCR recognition of peptide–MHC complexes on the surface of an APC and through signals provided at the same time by costimulators expressed on APCs.
• The best-defined costimulators are members of the B7 family, which are recognized by receptors of the CD28 family expressed on T cells. The expression of B7 costimulators on APCs is increased by encounter with microbes, providing a mechanism for generating optimal responses against infectious pathogens. Some members of the CD28 family inhibit T cell responses, and the outcome of T cell antigen recognition is determined by the balance between engagement of activating and inhibitory receptors of this family.
• T cell responses to antigen and costimulators include changes in the expression of surface molecules, synthesis of cytokines and cytokine receptors, cellular proliferation, and differentiation into effector and memory cells.

• The surface molecules whose expression is induced on T cell activation include proteins that are involved in retention of T cells in lymphoid
organs, growth factors for cytokines, effector and regulatory molecules,and molecules that influence migration of the T cells.

• Shortly after activation, T cells produce the cytokine IL-2 and express high levels of the functional IL-2R. IL-2 drives the proliferation of the cells, which can result in marked expansion of antigen-specific clones.

• Some activated T cells may differentiate into memory cells, which survive for long periods and respond rapidly to antigen challenge. The maintenance of memory cells is dependent on cytokines such as IL-7, which may promote the expression of antiapoptotic proteins and
stimulate low-level cycling. Memory T cells are heterogeneous and consist of populations that differ in migration properties and functional responses.

• T cell responses decline after elimination of the antigen, thus returning the system to rest. The decline is largely because the signals for continued lymphocyte activation are also eliminated.

• Cell-mediated immunity is the adaptive immune response stimulated by microbes inside host cells. It is mediated by T lymphocytes and can be
transferred from immunized to naive individuals by T cells and not by antibodies.

• CD4+ helper T lymphocytes may differentiate into specialized effector
Th1 cells that secrete IFN-γ, which mediate defense against intracellular microbes, or into Th2 cells that secrete IL-4 and IL-5, which favor IgEand
eosinophil/mast cell– mediated immune reactions against helminths, or into Th17 cells, which promote inflammation and mediate defense against extracellular fungi and bacteria.

• The differentiation of naive CD4+ T cells into subsets of effector cells is induced by cytokines produced by APCs, by the T cells themselves, and
by other cells. The differentiation program is governed by transcription
factors that promote cytokine gene expression in the T cells and epigenetic changes in cytokine gene loci, which may be associated with stable commitment to a particular subset. Each subset produces
cytokines that increase its own development and inhibit the development of the other subsets, thus leading to increasing polarization of the
response.

• CD4+ Th1 cells recognize antigens of microbes that have been ingested by phagocytes and activate the phagocytes to kill the microbes. The activation of macrophages by Th1 cells is mediated by IFN-γ and CD40LCD40 interactions. Activated macrophages kill phagocytosed microbes
ingested into phagolysosomes by the actions of reactive oxygen and nitrogen species and enzymes (called classical macrophage activation).

• Activated macrophages also stimulate inflammation and can damage tissues.

• CD4+ Th2 cells recognize antigens produced by helminths and other microbes, as well as environmental antigens associated with allergies. IL-4, secreted by activated Th2 cells or Tfh cells, promotes B cell isotype
switching and production of IgE, which may coat helminths and mediate mast cell degranulation and inflammation. IL-5 secreted by activated Th2 cells activates eosinophils to release granule contents that destroy
helminths but may also damage host tissues. IL-4 and IL-13 together provide protection at epithelial barriers and induce an alternative form of macrophage activation that generates macrophages that control inflammation and mediate tissue repair and fibrosis.

• CD4+ Th17 cells stimulate neutrophil-rich inflammatory responses that eradicate extracellular bacteria and fungi. Th17 cells may also be important in mediating tissue damage in autoimmune diseases.

• T cells of the CD8+ subset proliferate and differentiate into cytotoxic T lymphocytes (CTLs), which express cytotoxic granules and can kill
infected cells.

• The differentiation of CD8+ T cells into functional CTLs and memory cells requires recognition of antigen presented by dendritic cells, signals from CD4+ helper T cells in some situations, costimulation, and cytokines. Differentiation to CTLs involves the acquisition of the machinery to kill target cells and is driven by various transcription factors.

• CD8+ CTLs kill cells that express peptides derived from cytosolic antigens (e.g., viral antigens) that are presented in association with class I MHC molecules. CTL-mediated killing is mediated mainly by
granule exocytosis, which releases granzymes and perforin. Perforin facilitates granzyme entry into the cytoplasm of target cells, and
granzymes initiate the process of apoptosis.