Antigen presentation and peripheral tolerance T cells only recognize - PowerPoint PPT Presentation

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 ;