T cells Jan Novák

The immune system Protection against infectious agents Clearance of dying, damaged and dangerous cells Regulation of the immune responses

The immune system Non-specific defence mechanisms Innate immune system Adaptive immune system

The adaptive immune system T cells - cellular immune responses B cells – humoral immune responses

T cells Central role in the immune system Coordination of the immune response Cytotoxic functions Suppression of the immune responses

T cells versus B cells Minimal morphological differences Differentiation based on the detection of surface markers B cells: CD19, B220, T cells: TCR, CD3, CD4, CD5, CD8 etc.

T cell receptor (TCR) Antigen recognition (  + CD4/8 – MHC class I/II) Signalization (CD3 transmembrane complex) defosforilations Proliferation, differentiation, effector functions

Phenotype of T cells T cell receptor (TCR) Other receptors involved in the antigen recognition and signalization (CD4, CD8, CD3) Receptors and molecules involved in the migration of T cells Receptors for cytokines Activation markers (CD25, CD28, CD69)

T cells   - T cells CD4 helpers  Th1  Th2  Th3  Th17  CD4+CD25+ CD8 cytotoxic T cells iNKT (CD4+CD8- a CD4-CD8-)   T cells

10 The pathway of T cell development

Thymus

12 Today Thursday

TCR development The development of infinite repertoire of TCRs Each TCR of each T cell can recognize one antigen The repertoire of all TCR has the capacity to recognize any antigen

Formation of TCR repertoire  Organization of genes coding for TCR is similar to the genes coding for immunoglobulins  Gene complexes TCR  (TCR  )  gene complex for IgH  Gene complexes TCR  (TCR  )  gene complex for IgL

TCR development TCR is encoded by several gene segments V - variability D - diversity J - joining C - constant

TCR development Random rearrangement of V,D,J and C segments Recombination of gene segments (D-J, V- D) Recombination controlled by RAG

TCR development  Rearrangement of gene segments for  chains  Expression of pre-TCR   chain  CD3 complex  pre-  chain  Rearrangement of gene segments for  chains  Formation of definitive TCR

Central education/deletion

The maintenance of T cell tolerance

T cells   - T cells CD4 helpers  Th1  Th2  Th3  Th17  CD4+CD25+ CD8 cytotoxic T cells iNKT (CD4+CD8- a CD4-CD8-)   T cells

CD4+ T cell activation CD4+ T cell APC MHC class II – TCR-CD4 interaction Costimulation CD80/86-CD28

CD4+ T cells – T helpers Naive Th0 cell TCR – MHC interaction Engagement of costimulation pathways Cytokine milie IL-12 IL-4 TGF-  Th1 Th2 Th3 Th0 APC

Th1 cells Inflammatory cells Production of cytokines:  interferon (IFN) –   interleukin (IL) – 2  tumor necrosis factor (TNF) - 

Th1 cells Help to macrophages (M  ) Activation of M  (IFN–  Stimulation of their killing activities Elimination of intracellular agents Help to T cells Differentiate into Th1 profile (due to the IL- 12 production by APC) Secretion of autocrinne growth factor of T cells IL-2

Th1 cells Involved in the clearance of intracellular pathogens Involved in the delayed type of hypersensitivity Involved in some autoimmune diseases

Th2 cells Production of cytokines  IL-4  IL-5  IL-6  IL-13

Th2 cells Help to B cells Antibody production by B cells is dependent on the help of T cells (Th2) Cytokine dependent help: IL-4 Cell contact dependent help: CD40 (B cell) - CD154 (T cell) interaction Th3

Th2 cells Th3 T B T APC Specific (direct) helpNonspecific (bystander) help APC B

Th2 cells Participation in the defense against extracellular agents Participation in the allergic reactions Th3

Th1 – Th2 competition Th1 cytokines inhibit the development of Th2 responses Th2 cytokines inhibit the development of Th1 responses Th3

Th3 cells Develop in the presence of TGF- , IL-10 and IL-4 Secretion of TGF-  and IL-10 Induced after oral administration of antigens, play a role in the induction of oral tolerance Th3

Cytotoxic CD8+ T cells Elimination of dangerous cells Direct elimination of cells infected by intracellular pathogens Elimination of stressed cells (tumors, damaged cells)

Activation of CD8+ T cells CD8 APC CD4 CD4 help APC activation CD8 Somatic cell Recognition, activation MHC class I - TCR

Killing by CD8+ T cells Perforin-granzyme system (degranulation, perforation, apoptotic death) Fas-FasL interaction (apoptotic death) Cytokine dependent - lymphotoxin (apoptotic death) CD8 Somatic cell

Killing by CD8+ T cells – Perforin-granzyme system

Killing by CD8+ T cells – Fas – dependent killing

CD8+ T cells in immune reactions Clearance of infected cells – viruses, bacteria, parasites) Elimination of tumor cells in cooperation with NK cells Elimination of dying and damaged cells

Literature Immunobiology – The immune system in health and disease: Charles A. Janeway Jr., Garland Publishing, 2001 The autoimmune diseases: Noel A. Rose, Academic Press – Third edition, 1998 Medical Immunology: Tristam G. Parslow, Lange – Tenth edition, 2001 Nature Reviews Immunology