Cross Presentation of Dendritic Cells....#Medical #Biopharma #Research

INTRODUCTION
  MHC I molecules are expressed on all nucleated cells. The endogenous antigens or modified self-proteins are expressed on MHC I molecules in order to be detected by T-cells. CD8+ T-cells activation can occur when antigen is presented to them by Antigen Presenting Cells (APC). When APS are not affected directly, they acquire the exogenous antigen from infectious agents and then present them on MHC I. This phenomenon is known as cross presentation. 

 

INTRACELLULAR PATHWAYS OF CROSS PRESENTATION

Two main intracellular pathways of cross-presentation have been reported.

  • CYTOSOLIC PATHWAY

It is a pathway in which antigen is processed in the cytosol wherever the loading may occur. This pathway is sensitive to proteosome inhibitors. This suggests that internalized antigen access cytosol and is degraded by the proteosome. This degraded antigen is then transported to endoplasmic reticulum via transporter associated with antigen processing 1 (TAP 1) and TAP 2 where they are loaded on MHC I and then presented. Recruitment of MHC I loading complex and TAP to the endosomes and phagosomes indicate that peptide loading may also occur in such endocytic compartments. 

  • VACUOLAR PATHWAY

In this pathway antigen proteolysis and processing both occurs in endocytic compartments. This pathway is insensitive to proteosome inhibitors and is TAP-independent. But it shows sensitivity towards lysosomal proteolysis inhibitors. 

STEPS:

REGULATION OF ENDOCYTIC PH AND PROTEOLYTIC CLEAVAGE

Decreased proteolytic capacity of dendritic cells is one of the hallmarks of its endocytic pathways. Several models indicated that controlled proteolytic cleavage correlates with effective cross-presentation. When the antigens are exposed to highly proteolytic late endosomes, they are presented on MHC II. While when the antigens were exposed to less degradative early endosomes, they were presented on MHC I. antigens internalized via mannose receptor also favors cross presentation due to targeting the early endosome. Similarly, ligand nature also effects the cross presentation.

The decreased proteolysis in dendritic cells is due to decreased level of proteases. This is because of high PH level in endosomes that is the result of high activity of NOX 2 and low activity of V-ATPase. NOX 2 is basically stored in secretary lysosomes which get fused to phagosomes with the help of RAB27A. 

ER-PHAGOSOME CONNECTION

ER-resident proteins such as MHC I loading complex have been shown to reside in endocytic compartments of dendritic cells. Electron microscopy reveals the stacks of ER continuing towards phagosome being manufactured at plasma membrane. It has been proposed that SEC22B, which is an ER-resident SNARE, is involved in delivering the ER cargo to phagosomes.

ANTIGEN EXPORT TO THE CYTOSOLS

It has been reported the cross-presentation of antigen via cytosolic pathway requires the movement of antigen from endosomes to the cytosol. This was first demonstrated by indirect evidence that ribosome inactivating molecules inhibited protein synthesis. This concluded that these inactivating molecules were first phagocytosed and then delivered to cytosol where they were able to interact with ribosome. Evidence was later confirmed by electron microscopy.

More recently, the phenomenon was confirmed by apoptosis which was induced by exogenous cytochrome C. after internalization it was transferred to cytosol by cross-presenting cells only where it activated caspase-dependent apoptotic pathway. ERAD proteins p91 and SEC61 are involved in this transporting mechanism. 

CROSS PRESENTATION IN CANCER

Dendritic cells are found to reside tumor cells. But the subtype of these tumor infiltrating dendritic cells is still unclear. The defective CD8+ and CD103+ dendritic cells result in poor immunogenic response of Cytotoxic T-cells against such immunogenic syngeneic tumors. This shows the role of cross presenting dendritic cells against tumors. According to recent reports, type I interferon is involved in enhancing cross presentation by decreasing proteolytic degradation and hence plays its role against tumor rejection.

It has been reported that impaired CD169+ also impair tumor rejection. However it is still unclear that whether it is because of DCs or macrophages, because both cells express CD169. 

CROSS PRESENTATION IN TOLERANCE

It has been reported that cross presentation can result in CD8+ T cell tolerance. It can be of two types.

o   CENTRAL TOLERANCE

Developing thymocytes are functionally inactivated by negative selection in thymus based on affinity for self derived peptides. The process requires expression of all immunogenic self antigens in the thymus. Antigen presentation by medullary thymic epithelial cells (mTECs) is implicated to delete self-specific CD8+ thymocytes. Autoimmune regulator expression (AIRE) results in proliferative arrest and then apoptosis in mTECs. These are then engulfed by thymic DCs and are cross presented.  

o   PERIPHERAL TOLERANCE

T-cells with low affinity for self antigens sometimes escape negative selection and access peripheral tissues. These harmful T cells are then controlled by multiple mechanisms. This is known as peripheral tolerance.

First reported pathway is that natural regulatory T-cells have major role. Secondly, such cells are cross presented by residing dendritic cells by a process referred as cross tolerance. CD8+ T cells were thought to involve in cross tolerance but now the role of CD8-  has also been reported.

So, peripheral tolerance to self antigens has been reported to rely on cross presentation of exogenous antigen by both lymph-node residing and migratory dendritic cells.

CONCLUSION:

Cross presentation phenomenon has been reported since 30 years back but its role in immunity against viral and tumor infections is still giving a vague image. Role of different subpopulation of specific dendritic cells is still under investigation. However the present knowledge can be utilized in several ways for further researches to target tumor and viral infections as well as for investigation purposes.

Reginald Swift