Friday, April 27, 2012

CCR5 (R5)-tropic HIV Susceptible CD4 T cells (HST).

What is it?
R5-tropic HIV Susceptible CD4 T cells (HST).
CD4 T cells that are susceptible to an infection by R5 (CCR5)-tropic HIV.

Why are they so important?
Because the lack of HST undoubtedly leads to AIDS and providing the HST with a homozygous mutant form of CCR5 (CCR5delta32) cured an AIDS patient by reconstituting an immune system.
Moreover, individuals who have homozygous mutant form of HST (CCR5delta32) are resistant to getting AIDS even in the presence of high titers of R5-tropic HIV.

Where do they reside in the body?
The majority of CD4 T lymphocytes is enriched in the lymphoid organs, lymph nodes and spleen after being generated/developed in the thymus by the positive and negative selection via MHC class II molecules.  However, the HST are enriched in non-lymphoid tissue.  This could be due to the fact that HST do not express a chemokine receptor CCR7.  Therefore the phenotype of HST is CCR5+CCR7-.  In addition, they share many characteristics with effector memory T cells, such as CD45RBhigh, CD62Llo, etc.  This is another important and specific topic that will be dealt in another essay.  It is also noteworthy that the number and the composition of CD4 T cells in the mucosal effector sites, such as gut, skin and lung, seem to be controlled by commensal microbiota, instead of an antigen presented by MHC class II molecules.  This also provides a clue that HST could be a different type of CD4 T cells, distinct from conventional CD4 T cells found in lymphoid organs.

How does HST work?  (A billion dollar question that has never been asked)
This question can be rephrased as "Why does the loss of the HST lead to AIDS"?  It needs a lot of fundamental understanding of HST before we try to develop a vaccine against HIV and AIDS.

This is my current theory, I mean, the THEORY.
  1. HST is not derived from thymus (extrathymic T cells).
  2. HST comes in two different forms, one with FoxP3 and the other without FoxP3 (FoxP3+ and FoxP3-).
  3. HST can become a variety of effector T cells, such as Th17, Th1-like, Th2-like and TFH.
  4. HST are activator for antigen presenting cells (that can induce maturation of APCs via CD40L-CD40 interaction).
  5. HST respond directly to the pathogen associated molecular pattern (PAMP) via pattern recognition receptor (PRR).
  6. The number and the proportion of HST in mucosal effector sites are governed by the commensal microbiota, instead of the presence or absence of peptide antigen presented by MHC class II molecules.
So, put them altogether,
HST are CD4 T cells mainly located in the gut mucosal effector sites.  Their main job at the mucosal effector sites is to make sure that there is no aberrant and unnecessary immune responses by suppressing immune responses (peace keeper, police, during non-pathologic condition).  They are doing this through the IL-10, TGF-b and FoxP3 mediated immune suppression. During infection, they can rapidly change their phenotypes and turn into a variety of effector T cells (it is called plasticity of T helper cell).  In other words, they are sentinels at the site where immune system directly contacting incoming pathogens.  Depending on the situation (pathogens encountered), once peace-keeping HST can become one or many of the effector T cells (in other words, police in action for protecting host until soldiers are involved).  They can become Th1- like, Th-2 like, Th17, or TFH cells, all depending on the nature of the pathogens.  They probably differentiate fast at the mucosal effector sites, not at the lymphoid organs.  Unlike the majority of CD4 T cells found in lymphoid organs, they react directly to the PAMP through the PRR expressed on HST, suggesting their expression of PRR, such as TLR or NLR.  Unlike CD4 T cells in lymphoid organs, the number and frequency of HST are governed by the presence and nature of commensal and incoming microbiota.  All in all, they seem to be totally different from CD4 T cells found in lymphoid organs.  This is the type of cells that will be missing when R5-tropic HIV infects and destroys them all.  Some cytokines and cytokine receptors will differentially express on HST.  IL-2, IL-15, IL-27 and their receptors could be different ones.

What will be the immunological outcome of lacking HST after being completely destroyed within a matter of weeks by R5-tropic HIV?  
In the absence of HST, incoming pathogens will get into our body without any resistance.  In addition, the growth of commensal microbiota will not be controlled and once beneficial commensals become harmful due to their overcrowding.  It is easy to imagine that the lining of the gut starts to leak due to an imbalance triggered by overgrowth of microorganisms, which is a common occurrence to the AIDS patients (leaky guts and microbial translocation).  When there is an imbalance in mucosal environment in healthy individuals, HST readily becomes Th17 cells and other effector T cells.  IL-17 produced by Th17 cells recruit neutrophils to the area and they start to kill (phagocytose) and control the unchecked growth of bacteria and other microbial organisms.  In addition, IL-22 produced by Th17 cells repair epithelial linings disrupted by outgrowing microorganisms.  The loss of Th17 cells is one of the characteristics of an AIDS patient.  HST can turn into the interferon-gamma (IFN-g) producing Th1-like or IL-4 producing Th2-like effector T cells without major differentiation process, which usually occurs in the lymphoid organs from naive T cells with a specific peptide antigen.  Conventional T cell differentiation will require several complex and time-consuming steps that involve antigen processing, naive T cell activation, proliferation and differentiation, which usually take more than a week.  Proliferation, and differentiation of HST could be a lot quicker and immediate to counter incoming pathogens, which are usually multiplying every hour or so.  Moreover, data are accumulating, which suggesting two different types of Th1 andTh2 cells. It is highly likely that generation of broad specificity neutralizing antibodies (bnAb) against HIV will require TFH, which could be derived from HST.  Should that be the case, current hopes of HIV vaccine trials to boost antibody mediated anti-HIV immunity will need careful evaluation of each step.  I will expand this part in another essay.

Can we protect HST from R5-tropic HIV infection and destruction?
Yes, theoretically in two different ways.  First, by blocking one of the two molecules CD4 and CCR5, from adhering by HIV.  Many investigations have been tried including decoy receptors and soluble form of these molecules and antagonist for these molecules.  They are all valuable methods to try, without much success yet.  But they are not vaccine approaches and will not educate our immune system.  It is a very challenging task.  The more you know about the underlying mechanism, it becomes much more complicated.  Sometimes, our current paradigm of immunology hinders the progress required to understand HIV pathogenesis.  The HIV did it to survive in our hostile environment.  Can we counter them?  I hope so, much sooner than later.  We still need to understand how they are doing it, if we can counter them appropriately.  It seems like a long process and will definitely require ingenious thoughts derived from "outside the box".

Key words
HST, R5-tropic, HIV, AIDS, CCR5delta32, CCR7, effector memory T cells, CD45RB, CD62L, commensal microbiota, mucosal effector sites, lymphoid organs, non-lymphoid organs, extrathymus, FoxP3, effector T cells, Th17, Th1, Th2 TFH, antigen presenting cells, pathogen associated molecular pattern (PAMP),  pattern recognition receptor (PRR), TLR, NLR (Nod-like receptor), interferon-gamma (IFN-g), IL-4, naive T cells, broad specificity neutralizing antibodies (bnAb), decoy receptor, antagonist

** In May 2012 Masopust's group reported that effector memory T cells resident in non-lymphoid tissue T(RM) are different from effector memory T cells (TEM) in lymphoid tissue.  This finding is 180 degree different from their original claim for a long period of time (for 10 years).  I hope that this is the beginning of recognizing HST as a new type of T cells different from non-HST.  Masopust and Lou Picker also wrote a review article on this issue called (dubbed Hidden Memory).  This is an exciting change for the development of HIV vaccine.

The followings were Copied from JI

 2012 May 15;188(10):4866-75. Epub 2012 Apr 13.

Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues.

Source

Abstract  Differentiation and maintenance of recirculating effector memory CD8 T cells (T(EM)) depends on prolonged cognate Ag stimulation. Whether similar pathways of differentiation exist for recently identified tissue-resident effector memory T cells (T(RM)), which contribute to rapid local protection upon pathogen re-exposure, is unknown. Memory CD8αβ(+) T cells within small intestine epithelium are well-characterized examples of T(RM), and they maintain a long-lived effector-like phenotype that is highly suggestive of persistent Ag stimulation. This study sought to define the sources and requirements for prolonged Ag stimulation in programming this differentiation state, including local stimulation via cognate or cross-reactive Ags derived from pathogens, microbial flora, or dietary proteins. Contrary to expectations, we found that prolonged cognate Ag stimulation was dispensable for intestinal T(RM) ontogeny. In fact, chronic antigenic stimulation skewed differentiation away from the canonical intestinal T cell phenotype. Resident memory signatures, CD69 and CD103, were expressed in many nonlymphoid tissues including intestine, stomach, kidney, reproductive tract, pancreas, brain, heart, and salivary gland and could be driven by cytokines. Moreover, TGF-β-driven CD103 expression was required for T(RM) maintenance within intestinal epithelium in vivo. Thus, induction and maintenance of long-lived effector-like intestinal T(RM) differed from classic models of T(EM) ontogeny and were programmed through a novel location-dependent pathway that was required for the persistence of local immunological memory.

Their original story

Masopust D, Vezys V, Wherry EJ, Barber DL, Ahmed R.
J Immunol. 2006 Feb 15;176(4):2079-83.

Abstract

Whether tissue microenvironment influences memory CD8 T cell differentiation is unclear. We demonstrate that virus-specific intraepithelial lymphocytes in gut resemble neither central nor effector memory CD8 T cells isolated from spleen or blood. This unique phenotype arises in situ within the gut, suggesting that anatomic location plays an inductive role in the memory differentiation program. In support of this hypothesis, memory CD8 T cells changed phenotype upon change in location. After transfer and in vivo restimulation, gut or spleen memory cells proliferated, disseminated into spleen and gut, and adopted the memory T cell phenotype characteristic of their new environment. Our data suggests that anatomic location directly impacts the memory T cell differentiation program.

Review paper
Hidden memories: frontline memory T cells and early pathogen interception.
Masopust D, Picker LJ.
J Immunol. 2012 Jun 15;188(12):5811-7. Review.

Immunologic memory reflects the ability of a host to more effectively respond to a re-encounter with a particular pathogen than the first encounter, and when a vaccine mimics the first encounter, comprises the basis of vaccine efficacy. For T cells, memory is often equated with the anamnestic response, the ability of secondary lymphoid tissue-based (central) memory T cells to respond to pathogen exposure with a more rapid and higher magnitude production and infection-site delivery of pathogen-specific effector cells than observed in naive hosts. However, increasing evidence supports a fundamentally different kind of T cell memory in which differentiated, long-lived effector memory T cells, prepositioned in sites of potential pathogen invasion or rapidly mobilized to such sites from blood and marginated pools, intercept and potentially control/eliminate pathogen within hours of infection. In this article, we review the evidence for this "hidden" T cell memory and its implication for vaccine development.





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