Immune Tolerance

Differentiate between Central and Peripheral Tolerance

• Location

• Mech

Central Tolerance:

• Location:

  • Primary/generative lymphoid tissues

• Mech:

  • T:

    • Negative selection in Thymus Medulla

    • Tregs Creation

  • B:

    • Receptor editing or deletion

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Peripheral Tolerance:

• Location:

  • Secondary/peripheral lymphoid tissues

• Mech:

  • via rDCs (inhibitory rather than stimulatory)

  • T/B cells anergy via Treg

  • T Cells Anergy

    • via inhibitory receptors or lack of Signal 2

      • CTLA-4, PD-1

    • Via autophagy inhibition

Describe the 2 mechanism of T Cell Inhibition

T cell Inhibition Mech:

1. CTLA-4 (T) - CD80/CD86 (AKA B7, on APC) → rips it out of APC cell membrane → endocytosis → degradation

2. PD1 (T) - PD1L1/2 (APC) → inhibits signal 1/2

Describe the Development & Function of T Regulatory Cells

Describe the 3 proposed mechanisms for Accumulation of Colonic Treg Cells

Mech:

1. Differentiation of pTreg cells

   • Env rich in TGFβ, retinoic acid, microbial antigens/metabolites → Differentation of pTreg from naive CD4+ T cells

2. Recruitment and proliferation of tTreg cells

   1. tTreg are selected by self antigens in thymus → upregulates gut-homing receptors,

      • α4β7 integrin

      • CCR9

      • GPR15

   2. encounter intestinal environment →

      • Retinoic acid upregulates α4β7 integrin + CCR9

      • SCFAs induce expression of GPR15 on Treg cells.

   3. accumulated tTreg cells recognize antigens → proliferation

3. Treg cell niche maintenance

   • microbiota stimuli → create + maintain Treg cell niche

     • → tTreg cells migration + proliferation via

       • IL-2

       • MHC class II-dependent antigen presentation

Describe Autophagy

• Definition

• Function of Autophagy Inhibition

• Mech

  • T-Cell Act.

  • T-Cell Anergy

Autophagy:

• Definition:

  • tolerance-avoidance mechanism via Metabolism modulation + signal pathways

    • allows T cell effector response and avoids anergy

• Inhibition of Autophagy Function:

  • induces tolerance and prevents autoimmunity.

• Mech:

  • T Cell Activation

    • Binding to IL-2R → PTPN1 autophagolysosome → allows TCR/CD28 to induce Act. genes via Fos/Jun + NFAT

  • T Cell Anergy

    • No binding to IL-2R → PTPN1 inhibits TCR/CD28 Signaling → NFAT induces Anergy Genes

Draw out the Damage-Response Framework and list the tenants

Tenants:

1. Microbial pathogenesis = outcome of interaction btw host/microorganism.

2. host-relevant outcome of interaction = amount of damage to the host.

3. Host damage = microbial factors + host immune response.

Draw out the Damage-Response Framework for Pathogens that only cause damage in the setting of weak immune responses.

Draw out the Damage-Response Framework for Pathogens that cause damage either in hosts with weak immune responses or in the setting of normal host responses.

Draw out the Damage-Response Framework for Pathogens that cause damage during any immune response but cause the most damage at either extreme of the host response continuum.

Draw out the Damage-Response Framework for Pathogens that cause the most damage at the weak and strong extremes of the response continuum.

Draw out the Damage-Response Framework for Pathogens that cause damage all along the response continuum, but damage can be enhanced by strong immune responses.

Draw out the Damage-Response Framework for Pathogens that only cause damage in the context of strong immune responses.