Are MSC-exosomes attacked by immune cells?

When utilizing extracellular vesicles (EVs) as a therapeutic approach, it is important to consider the issue of immune rejection. During cell transplantation, immune rejection is always a concern, especially in the case of allogeneic transplantation (transplanting cells from another individual). The transplanted cells are often attacked by the recipient’s immune cells, making it difficult for them to engraft in the body. This is why immunosuppressants are necessary for allogeneic stem cell transplantation.

Exosomes derived from mesenchymal stem cells (MSCs) have been suggested to address this problem and make allogeneic transplantation and administration possible. However, it has been reported that exosomes also express Major Histocompatibility Complex (MHC), which serves as a marker to determine whether immune cells will attack or ignore them. So, how can exosomes evade immune cell attacks?

In this article, we will discuss Major Histocompatibility Complex (MHC) in relation to Mesenchymal Stem Cells (MSCs) and exosomes to provide an explanation.

Definition and Role of MHC

Major Histocompatibility Complex (MHC) is a group of genes that encode cell surface proteins for the immune system to recognize foreign substances. But why is MHC important?

Importance of MHC in Immune Response

The role of MHC is similar to a security checkpoint at an airport in the immune response. MHC proteins present antigens, which act as “passengers,” to T cells, facilitating the quick handling of harmful substances.

MHC is a specialized protein present on the cell surface, and it plays a crucial role in distinguishing self from non-self. The main job of MHC is to capture foreign substances (e.g., parts of viruses or bacteria) inside cells and present them on the cell surface. This process provides “information” to other components of the immune system, particularly T cells, to initiate an attack.

There are mainly two types of MHC:

MHC class I is present on all nucleated cells (i.e., most cells in the body) and primarily identifies infected cells or cancer cells. These cells typically produce abnormal proteins, and MHC class I presents these abnormal proteins to T cells.

The cells that recognize MHC class I molecules are mainly:

1. CD8+ T cells: These cells recognize antigens presented by MHC class I molecules. CD8+ T cells directly attack abnormal cells, such as virus-infected cells or cancer cells. Antigens bound to MHC class I molecules are recognized by CD8+ T cells through the T-cell receptor (TCR), resulting in the activation of CD8+ T cells and granting them the ability to kill the targeted cells.
2. Natural Killer (NK) cells: NK cells also recognize MHC class I molecules present on the cell surface. However, NK cells recognize the presence of MHC class I molecules as a “self” signal and typically refrain from attacking when it is present. However, when cells do not express MHC class I molecules, as in the case of viral infections or cancer, NK cells perceive it as abnormality and attack those cells.

Therefore, CD8+ T cells and NK cells recognize MHC class I molecules, but their recognition methods and outcomes differ.

On the other hand, MHC class II is mainly present on specific cells called antigen-presenting cells (APCs), which are part of the immune system. These cells capture and break down foreign substances that invade the body and transport them to MHC class II for presentation on the cell surface. They primarily present antigens to helper T cells, initiating an immune response.

Thus, MHC acts as a “flagship” of cells, indicating whether they are healthy, infected by pathogens, or showing other abnormalities. This allows the immune system to determine which cells to attack and which cells to ignore. Therefore, MHC is an essential element in controlling the immune response and protecting the body.

Understanding MSCs and Their Characteristics

Next, let’s take a closer look at Mesenchymal Stem Cells (MSCs), which are multifunctional stem cells.

Origin and Function of MSCs

MSCs are derived from the stromal cells of various tissues and possess the ability to differentiate into various cell types, playing a crucial role in the field of regenerative medicine. But what makes them unique? Learn more here.

Immunomodulatory Properties of MSCs

Mesenchymal Stem Cells (MSCs) are not only known for their broad differentiation capabilities but also for their powerful immunomodulatory properties. MSCs act on various immune cells to regulate their functions, thereby controlling the immune response. The immunomodulatory abilities of MSCs have significant implications in inflammation suppression, tissue repair, and the treatment of autoimmune diseases and graft-versus-host disease (GvHD) in the field of medical applications.

Here are some of the mechanisms by which MSCs modulate the immune response:

1. T cell suppression: MSCs can inhibit the proliferation and function of T cells. This is mainly achieved by secreting molecules such as nitric oxide (NO), prostaglandin E2 (PGE2), transforming growth factor-beta (TGF-β), interleukin-10 (IL-10), and human leukocyte antigen-G5 (HLA-G5).
2. B cell suppression: MSCs have been reported to inhibit the proliferation, differentiation, and antibody production of B cells. This process also depends on the secretion of PGE2, TGF-β, and IL-10.
3. Natural Killer (NK) cell suppression: MSCs suppress the cytotoxicity and proliferation of NK cells. This is achieved mainly by inhibiting the effects of interleukin-2 (IL-2) and interleukin-15 (IL-15), along with the secretion of PGE2, TGF-β, and interleukin-6 (IL-6).
4. Antigen-presenting cell (APC) suppression: MSCs inhibit the maturation and function of dendritic cells (a type of APC). They do this by suppressing the expression of MHC class II and co-stimulatory molecules (CD80, CD86), thereby reducing the antigen-presenting capacity to T cells.

Through these mechanisms, MSCs control the immune response and maintain a proper balance. Therefore, MSCs have become crucial cells in the field of immunomodulatory therapy and regenerative medicine treatment strategies.

How Do Immune Cells Recognize and Attack Particles or Whole Cells (e.g., Bacteria or Viruses)?

The mechanisms by which immune cells recognize and attack particles or whole cells (e.g., bacteria or viruses) are mainly based on the following processes:

1. Recognition through Pattern Recognition Receptors (PRRs): Immune cells utilize specific types of receptors called Pattern Recognition Receptors (PRRs) to recognize unique structural patterns (PAMPs or DAMPs) of foreign substances or pathogens.
2. Phagocytosis: Some immune cells (e.g., macrophages and neutrophils) have the ability to engulf entire pathogens such as bacteria. These cells internalize the pathogens, break them down in intracellular vesicles called lysosomes, and ultimately destroy them.
3. Antigen presentation: Cells that have undergone phagocytosis present fragments (antigens) of the digested pathogen on MHC molecules, displaying them on the cell surface. T cells that recognize these antigens initiate an immune response.
4. Role of Natural Killer (NK) Cells: NK cells have the ability to distinguish self from non-self cells. When specific ligands are recognized or the absence of MHC class I molecules is detected, NK cells attack those cells.

Thus, the immune system recognizes and attacks viruses, bacteria, parasites, and other pathogens through various mechanisms. These mechanisms function in both the early stages (innate immune response) and later stages (adaptive immune response) of the immune response.

Exosomes: Tiny Particles with Significant Roles

Exosomes are tiny vesicles that play important roles in intercellular communication. Learn more here.

Exosomes in Intercellular Communication

These nanosized vesicles transport proteins, lipids, and nucleic acids from one cell to another, influencing various physiological and pathological processes. They can be thought of as text messages between cells.

Expression of MHC on MSC-Derived Exosomes

MHC class 1

Exosomes derived from Mesenchymal Stem Cells (MSCs) have the ability to carry information such as proteins, RNA, DNA, etc., from the parent cells to other cells. Therefore, it is possible that the exosomes derived from MSCs may also contain the MHC class 1 molecules expressed by the MSCs.

However, MSCs themselves are known to have immunosuppressive properties and relatively low expression of MHC class 1 molecules. Therefore, the level of MHC class 1 in MSC-derived exosomes may also be limited.

Additionally, the composition of exosomes can vary significantly depending on the cell’s state and culture conditions. Hence, it is not guaranteed that MSC-derived exosomes always contain MHC class 1 molecules.

MHC class 2

MSCs have minimal expression of MHC class 2 molecules; therefore, MSC-derived exosomes may also have limited expression of MHC molecules. This may make exosomes less visible to the immune system. However, the expression of MHC by MSCs is known to be influenced by the environment. Under inflammatory conditions or in the presence of specific cytokines (such as interferon-gamma), MSCs have been reported to increase the expression of MHC class 1 and class 2 molecules. Enhanced MHC expression under such conditions may impact the immunoregulatory function of MSCs.

Can MSC Exosomes Themselves Be Immunologically Rejected?

As mentioned earlier, cells that recognize MHC class 1 mainly include CD8 T cells and NK cells. So, can CD8 T cells and NK cells attack non-self MSC exosomes?

Potential for Activation of CD8 T Cells and NK Cells, but…

CD8+ T cells and NK cells are primarily involved in immune responses against cells themselves. While these cells have the ability to attack abnormal cells, they generally do not directly attack small particles such as exosomes.

Exosomes are very small vesicles (approximately 30-150nm in diameter) secreted by cells, and they carry various biological substances (such as proteins, lipoproteins, RNA, DNA, etc.). Due to their small size and structural characteristics, exosomes are less likely to be recognized as “cells” by the immune system.

However, since exosomes have various proteins and antigens on their surface, they have the potential to induce immune responses. Particularly, when exosomes contain non-self antigens or are secreted by abnormal cells, these antigens can be recognized by antigen-presenting cells (APCs), potentially leading to the activation of T cells. Therefore, exosomes can indirectly induce the response of CD8+ T cells, but they do not directly “attack” them.

Similarly, NK cells do not directly attack exosomes. NK cells mainly recognize and attack cells, and their activity is primarily regulated by the presence or absence of MHC class 1 molecules on the cell surface. However, the extent to which exosomes may indirectly influence NK cell activation is not yet fully understood.

Low Expression of Costimulatory Molecules

Costimulatory molecules refer to a set of molecules that provide the second signal necessary for activating T cells. These molecules exist on antigen-presenting cells (APCs) and assist in the activation of T cells when the first signal of antigen recognition by the T cell receptor (TCR) alone is insufficient. Some examples of costimulatory molecules include:

1. CD28: CD28 on T cells interacts with the B7 molecule family (CD80 or CD86) on APCs. This is a typical costimulatory interaction that promotes T cell activation and proliferation.
2. CD40L (CD154): CD40L on T cells interacts with CD40 on APCs, assisting in T cell activation. The interaction between CD40 and CD40L is particularly important between helper T cells (CD4+ T cells) and B cells.
3. ICOS (Inducible Co-Stimulator): ICOS is a molecule on T cells belonging to the CD28 family, which binds to ICOSL on APCs. The signal from ICOS is particularly important for the function of follicular helper T cells.

These are just a few examples, and there are many other costimulatory molecules. Each molecule plays specialized roles in specific immune responses or cell types.

However, the expression of CD28, CD154 (CD40L), and ICOS on Mesenchymal Stem Cells (MSCs) is generally considered to be very low or absent. Typically, these molecules are predominantly expressed on T cells or antigen-presenting cells (APCs), playing crucial roles in the regulation of immune responses. For example, CD28 and CD154 (CD40L) are mainly found on T cells, and ICOS is particularly seen on activated T cells.

Therefore, it is not expected that these molecules are expressed on MSCs. MSCs have their own unique roles in interaction with the immune system, and part of that involves expressing specific cell surface molecules.

What Mechanisms Cause MHC to Induce Immune Rejection?

The mechanisms by which Major Histocompatibility Complex (MHC) molecules induce immune rejection are as follows:

1. MHC class 1 and class 2 molecules play a role in conveying the state of the host cells to the body’s immune system. Specifically, they capture peptides generated inside the cells and present them on their surface to immune cells such as T cells, thereby conveying that information.
2. Normally, peptides bound to self-MHC molecules are not recognized and attacked by the host’s immune system. However, in the case of transplantation, if the MHC molecules of the donor and recipient (host) do not match, the donor’s MHC molecules are recognized as “non-self” within the recipient’s body.
3. The recipient’s immune system perceives the donor-derived “non-self” MHC molecules as foreign and initiates an immune response (attack) against them. This forms the basic mechanism of graft-versus-host disease (GvHD) and transplant rejection.
4. To prevent this reaction, the compatibility of MHC molecules is evaluated between the donor and recipient before transplantation. The higher the compatibility, the lower the risk of transplant rejection.

Therefore, the compatibility of MHC molecules is a crucial factor in the success of transplantation. However, through the use of immunosuppressive drugs to control the body’s immune response, transplantation may still be possible even if the compatibility of MHC molecules is not perfect.

These findings open new prospects for research in immunology, exosome biology, and the therapeutic applications of MSCs.

Conclusion

Understanding the relationship between MHC expression on MSC-derived exosomes and autoimmune rejection is important in harnessing the therapeutic potential of MSCs and exosomes. The intricate interplay of these elements, akin to the complex steps of a ballet, captivates researchers and promises exciting leaps in the future.

Frequently Asked Questions

1. What is MHC? MHC stands for Major Histocompatibility Complex, which is a group of genes that encode cell surface proteins involved in the recognition of foreign substances by the immune system.

2. What are the specific characteristics of MSCs? MSCs are stem cells derived from the stromal cells of various tissues, and they have the ability to differentiate into various cell types. They also possess immunomodulatory properties.

3. How do exosomes participate in intercellular communication? Exosomes transport proteins, lipids, nucleic acids, and other biological substances from one cell to another, playing a crucial role in intercellular information transfer.

4. How does MHC expression on MSC-derived exosomes affect immune rejection? The MHC expression on MSC-derived exosomes can influence the interaction with immune cells and potentially induce immune rejection.

5. What potential impact can these interactions have on future research and therapies? Understanding these interactions has the potential to open up new perspectives in immunology, exosome biology, and the therapeutic applications of MSCs.

Reference Papers

1. Phinney, D. G., & Pittenger, M. F. (2017). Concise Review: MSC‐Derived Exosomes for Cell‐Free Therapy. Stem Cells, 35(4), 851-858.
   • This paper focuses on the extracellular therapeutic potential of MSC-derived exosomes and also discusses the immunomodulatory effects of exosomes and their impact on immune responses.
2. Del Fattore, A., Luciano, R., Pascucci, L., Goffredo, B. M., Giorda, E., Scapaticci, M., … & Muraca, M. (2015). Immunoregulatory Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles on T Lymphocytes. Cell Transplantation, 24(12), 2615-2627.
   • This paper provides detailed insights into the immunoregulatory effects of MSC-derived exosomes on T lymphocytes.
3. Di Trapani, M., Bassi, G., Midolo, M., Gatti, A., Kamga, P. T., Cassaro, A., … & Adamo, A. (2016). Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Scientific Reports, 6, 24120.
   • This paper investigates how MSC-derived exosomes affect the functions of T cells, B cells, and NK cells.

These papers explore the relationship between MSC-derived exosomes and immune cells from different angles, and they would be useful in deepening the understanding of whether MSC-derived exosomes are attacked by immune cells. However, based on current scientific knowledge and understanding, it is generally believed that MSC-derived exosomes primarily possess immunomodulatory effects and are less prone to attack by immune cells.