JPEMS 2014 Basic Immunology module Activation and functions of T lymphocytes Teacher: Pr. Régis Josien, Laboratoire d Immunologie, CHU Nantes Regis.Josien@univ-nantes.fr 1
An#gen recogni#on by T cells T cells, via their TCR, recognize an4genic pep4des presented by MHC molecules Endogenous pep4des (ex: virus): MHC class I / CD8+T cells Exogenous pep4des (extacellular pathogens): MHC class II / CD4+ T cells Ag presenta4on to naive T cell require specialized an4gen presen4ng cells = dendri4c cells Effector T cells target host cells (ex: macrophages) and not directly pathogens
Cell mediated immunity T cells are cri4cal in cell- mediated immunity T cells are required to fight intracellular pathogens and Some T cells also play a important role in figh4ng extracellular pathogens: By helping B cells to produce Ab (role of T FH cells) By inducing inflammatory responses at epithelial sites (role of Th17 cells)
Types of intracellular microbes combated by T cell- mediated immunity
Steps in ac#va#on of T lymphocytes
Circula#on of naive T cells
Naive T cells recognize Ag presented by DC in secondary lymphoid organs
Mechanisms of naive T cell migra#on to lymph node CCR7 HEV CCL21/SLC
Lymphocyte trafick
T cell integrins
The role of dendri#c cells
Matura#on and migra#on of DC
Ligand- receptor pairs involved in T cell ac#va#on
An#gen recogni#on and signal transduc#on during T cell ac#va#on
Regula#on of integrin ac#vity by TCR signaling
The role of cos#mula#on in T cell ac#va#on
Three signals are necessary to activate naive T cells (CD80) (CD86) 17
Role of CTLA4 (CD152) in the inhibi#on of T cell ac#va#on PD- 1 is another inhibitory receptor on T cells Monoclonal an#bodies to CTLA4 and PD- 1 are now used in cancer pa#ents to enhance an#- tumor immune responses with great efficacy
Ac#va#on of CD8+T cells
Proteins produced by an#gen- s#mulated T cells
Signal transduc#on pathways in T lymphocytes Immunosuppressive drugs: - Ciclosporine A/ tacrolimus: calcineurin inhibitors - Rapamycine: mtor inhibitors
Steps in ac#va#on of T lymphocytes
The role of IL- 2 and IL- 2R in T cell prolifera#on Monoclonal an4bodies to IL- 2Rγ chain (CD25) are rou4nely used in transplanted pa4ent to inhibit gra[ rejec4on
Expansion and decline of T cell responses Clonal expansion : - T CD4: 100 à 1000 x - T CD8: >10000 x
Proper#es of the major cytokines produced by Th cells
Molecules involved in effector func#ons of Th cells 2 types of signals delivered by effector Th cells: - Membrane molecules: CD40L - Cytokines + chemokines Main target cells are - Macrophages - B lymphocytes There are several subsets of Th cells that are dis#nguished by cytokines they produce
General proper#es of effector T cells Ac#va#on of effector cells does not require cos#mula#on
The development and characteris#cs of subsets of Th cells
The func#ons of Th1 cells
The func#ons of Th2 cells Monoclonal an4bodies against IL- 5 have shown efficacy in treatement eosinophilic asthma
The func#ons of Th17 cells Monoclonal an4bodies to IL- 17 are used to treat immune- mediated inflammatory diseases (rheumatoid arthri4s, psoriasis)
The development of Th effector cells
Effector Th cells and immunopathology Autoimmunity Inflammatory disease Autoimmunity Allergy 33
CD8+ T cells differen4ate in cytotoxic T lymphocte (CTL) Proper#es of effector T cells
Mechanisms of killing of infected cells by CD8+ CTL
The immune synapse
Immunological synapse
h_p://www.cbr.med.harvard.edu/labs/vonandrian/pages/videos%20page.html
h_p://www.cbr.med.harvard.edu/labs/vonandrian/pages/videos%20page.html 39
DC: T cell interactions Short-lived interactions (no Ag recognition) Long-lived interactions (Ag recognition) h_p://www.cbr.med.harvard.edu/labs/vonandrian/pages/videos%20page.html 40
41
Migra#on of effector T cells
Phenotype of naive and ac#vated T cells CCR7 - +
Steps in ac#va#on of T lymphocytes
Memory T cells Likely derived from effector T cells Their survival is dependent on cytokines (IL- 7, IL- 15) Rapidly (24h) ac4vated in response to Ag 3 classes of memory T cells Central memory T cells (T CM ): circulate in lymphoid organs and blood, rapid clonal expansion and differen4a4on Effector memory T cells (T EM ): circulate in blood, spleen and some 4ssues (not epith); rapid effector func4ons Resident memory cells (T RM ): do not recirculate; found in epithelia (skin, gut, vagina), lung: rapid effector func4ons in at sites of exposure (epith).