Antigen presentation and peripheral tolerance
T cells only recognize antigens presented in the MHC context
characteristics Características Molécula que se liga ao antígeno Molecules bound to antigens Imunoglobulina (Ig) Receptor de células Moléculas de MHC* Immunoglobulin MHC TCR T(TCR) Sítio de ligação ao 3 regiões CDR nas 3 regiões CDR nas Fenda para ligação de 3 CDRs in the alpha Binding site 3 CDRs in the light and Peptide grooves in the antígeno porções variáveis das porções variáveis α e β peptídeo formada pelas and beta variable heavy variable chains α 1/ β 1 chains in II; cadeias leve e pesada cadeias α 1 e β 1 em chains In α 1/ α 2 chain in I classe II e α 1 α 2 em classe I Tipo de antígeno antigen Macromolecules, organic MHC/peptide complex Peptídeos peptides Molecules, proteins, lipids, Sugars … Antigen nature Linear or conformacional Linear; 2 to 3 aa residues Linear; 8 to 12 aa depending on the MHC molecule Binding affinity K d 10 -7 - 10 -11 M; K d 10 -5 - 10 -7 M K d 10 -6 - 10 -9 M; durable Affinity maturation interaction
T cell receptor complex
Characteristics II
Antigen presentation pathways
Class II pathway
HLA-DO ensures peptide presentation diversity
Class I pathway
Proteoasome and immunoproteasome
Immunoproteasome cleaves proteins preferentially after basic and hydrophobic residues generating peptides with higher affinity to MHC-I
CROSS-PRESENTATION how can a DC activate a CD8 T cell response if it is not infected by a virus?
PROFESSIONAL ANTIGEN PRESENTING CELLS
Function – antigen presentation Antigen -
Location, location, location…… http://www.youtube.com/watch?v=Kh- XdNnTZUo&feature=player_embedded
1 st and 2 nd signals for lymphocyte activation, origin of 2 nd signals -
- Activation of T cells Immunological synapse
Co-stimulatory molecules family
Co-stimulation co-stimulation B7.1/B7.2 or CD80/CD86 Stabilization of NFAT Activation of other txn factors
Stabilization of NFAT signaling Diehn et al, PNAS, 18, 11796 (2002)
Activation of other transcription factors
IL-2 and its receptor
PERIPHERAL TOLERANCE Tolerance to self or non harmful antigens triggered in the peripheral tissues. 1 - anergy 2- apoptosis (co-stimulus induce the anti-apoptotic protein Bcl-xL) 3 – Regulatory phenotype induction – dependent on the microenvironment
REGULATORY T CELLS naturais TGF b , IL-10 induzidas kinurenina
FUNCTION – MECHANISMS OF ACTION INDUÇÃO DE MORTE CELULAR EXPRESSÃO DE CITOCINAS INIBIDORAS INDUÇÃO DE TOLERÂNCIA EM DC ALTERAÇÕES METABÓLICAS mecanismo extrínsico de CTLA4 MORTE POR FALTA DE IL-2 INIBIÇÃO DE MATURAÇÃO E FUNÇÃO
Tregs convert ATP in adenosine – a suppressor molecule
Tregs express high levels of CD25 and quench IL-2 from the environment
Tregs limit the proliferation rate of effector T cells https://doi.org/10.3389/fimmu.2018.02461
Oral tolerance Tolerance to antigens acquired through the oral and digestive tract/nasal TGF b expression TGF b e IL-10 rich mucosa – Treg inducion
Indução de T reguladoras na mucosa intestinal
Células dendríticas produtoras de ácido retinóico também participam do processo de tolerância - RAR (receptor de ácido retinóico) liga-se a elementos resposivos no promotor de genes como CCR9 garantindo a migração de células reguladoras e linfócitos B produtores de IgA para a mucosa; - RA induz fenótipo regulador em linfócitos T, cooperando com TGF b ;
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