Highlights:
- Define effector CD4 T cells
- Loss of effector memory CD4 T cells in HIV infected individuals
- Current paradigms on the generation of effector CD4 T cells
- Current paradigms on the role of effector CD4 T cells in protective immunity
Effector CD4 T cells are pre-differentiated CD4 T cells that can perform a variety of effector function when challenged by a cell specific antigen Several types of effector CD4 T cells, such as Th1, Th2, Th17, TFH and Treg cells, perform various effector functions. These cells distinguish themselves by their characteristic cytokines produced during proliferation and their cell specific transcription factors for each type of effector T cells. To become a specific effector CD4 T cells, they require a specific cytokine during activation/differentiation steps. Details of cytokines required to become each effector T cells and cytokines produced by each of them can be found in many other places, including free web sites, such as wikipedia. (for example, Th17 cells in wikipedia: http://en.wikipedia.org/wiki/T_helper_17_cell).
Loss of effector CD4 T cells in HIV infected individuals:
The specific loss of effector CD4 T cells during and after HIV infection.
The information on the loss of a specific type of effector T cells in HIV infected individuals or selective susceptibility of CD4 T cells by HIV infection will provide an invaluable information not only on the origin of effector T cells, but also on HIV pathogenesis. The loss of Th17 cells in HIV (or SIV) infected individuals (non-human primates) is well established by many groups. The loss of IFN-g producing cells in acute SIV infection (Dandekar's group in Nature Medicine) and that of Treg cells found in LP of gut, but not those in lymphoid organs and blood (Chase et al. by Siliciano group JVI 2007 Severe depletion of CD4+ CD25+ regulatory T cells from the intestinal lamina propria but not peripheral blood or lymph nodes during acute simian immunodeficiency virus infection) are not well known.
In addition, CCR5+CCR6+ IFN-g producing Th1 or CCR5+CCR6+ IL-4 producing Th2 cells are susceptible to HIV infection, while conventional Th1 or Th2 cells (both are CCR6-CCR5-) are resistant to HIV infection (Rafick Sekaly;s group in JI. 2010 Peripheral blood CCR4+CCR6+ and CXCR3+CCR6+CD4+ T cells are highly permissive toHIV-1 infection). This suggests that even the IFN-g or IL-4 producing Th1 or Th2 cells are two different types with regards to HIV susceptibility and expressions of chemokine receptors.
Th17: It has been established that certain effector CD4 T cells are selectively affected by an HIV infection. The loss of Th17 cells during HIV infection is the first one with wide acceptance. A special issue was published on the subject of the gut and Th17 in HIV infection (13 reviews and an editorial in an issue of Current Opinions in HIV and AIDS: The gut and Th17 in HIV infection: http://journals.lww.com/co-hivandaids/toc/2010/03000 )
Even with these extensive research by many investigators, there is no clear explanation why Th17 cells are missing in HIV infected individuals. Not a single article questioned about the origin of Th17 cells could be CCR5+CD4 T cells that are susceptible to R5-tropic HIV (HST), and still don't. I will offer my view in a separate discussion, which is different from all of them later.
TFH: Is there a loss of TFH cells in HIV infected individuals, which has a very significant impact on HIV vaccine development utilizing BnAb? This issue requires a special attention in HIV pathogenesis and HIV vaccine development. However, it has not been studied extensively yet due to our understanding of TFH is still an infant stage. The presence and the role of TFH in HIV infected individuals is a very important issue, in particular, since the effector function mediated by TFH is critical to generate high affinity antibody generation. TFH is involved in several steps of B cell maturation, including an isotype switching followed by an affinity maturation. Early part of the B cell maturation can occur at an extrafollicular stage even before generating germinal center, while affinity maturation occurs at the germinal center after formation. Both steps require a transcription factor Bcl-6 expressing TFH cells, although they could be two different different types of TFH cells. You can imagine that loss of an early emerging TFH cells could impact severely on the generation of broad neutralizing antibody (BnAb). Are they affected by HIV infection? There isn't any study directly asking that specific question, unlike Th17 cells in HIV infection. However, a study by Klatt et al., (SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination. Klatt NR, Vinton CL, Lynch RM, Canary LA, Ho J, Darrah PA, Estes JD, Seder RA, Moir SL,Brenchley JM. Blood. 2011 Nov 24;118(22):5803-12. Epub 2011 Sep 29.) suggests that there is a possibility that TFH cells could be missing in action during SIV infected non-human primates. If that will be the case, an HIV vaccine strategy generating the broad neutralizing antibody against the HIV env protein (gp120) needs to be evaluated with caution. It will also explain why it has been so difficult to generate neutralizing antibodies against HIV even after many well-managed trials. My inclination on this issue is that early appearing TFH cells, extrafollicular TFH, could be derived (differentiated) from the HST. If that will be the case, loss of HST by HIV infection, will severely hamper the generation of high affinity neutralizing antibodies, especially an isotype switched, IgG type, antibody. It will be interesting to see whether the secretion of IgA type antibody also requires extrafollicular TFH cells or not, since accumulation of IgA type antibody negatively affected HIV vaccine efficacy in RV144 trial.
Th1: Th1 cells can be generated in vitro (or ex vivo meaning outside the body in an artificial tissue culture system) by stimulating naive CD4 T cells in the presence of IL-12. After 3 to 5 days of culture in conditioned media, CD4 T cells that were differentiated into Th1 cells produce IFN-g when re-stimulated. It is a very slow process inside the body, since there are very few antigen specific CD4 T cells. Therefore, it usually takes several weeks to generate enough antigen specific Th1 type CD4 T cells. There is a surprise in HIV pathogenesis considering a very few HIV specific CD4 T cells in the body. In this case, SIV specific CD4 T cells. During SIV infection, there is a sudden burst (4 hours after infection) of mRNA expressions of IL-17 and IFN-g in small intestine ileal loops. This unexpected data suggest that certain Th1-like cells and Th17 cells are preexist in GI tract mucosal area. Those IFN-g producing Th1-like cells may not be the typical antigen specific Th1 cells. Production of IL-17 and IFN-g by these cells cannot be detected in SIV infected animals (Rhesus macaque), suggesting that CCR5 expressing CD4 T cells (HST: CD4 T cells susceptible to R5-tropic HIV) could be the source for the IFN-g producing cells.
Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE, Godinez I, Sankaran S, Paixao TA, Gordon MA, Kolls JK, Dandekar S, Bäumler AJ.
Nat Med. 2008 Apr;14(4):421-8. Epub 2008 Mar 23.).
Current paradigms on the generation of effector CD4 T cells
Current paradigms on the generation of effector CD4 T cells are rather simple and straightforward, although it takes more than two decades to establish them since the first use of terms, type 1 and type 2 CD4 T helper cells, Th1 and Th2, in 1986. It is assumed that all effector CD4 T cells are derived from the naive T cells, directly exported from the thymus after T cell development and moved to lymph nodes, where the majority of naive T cells are found. Naive T cells are defined as T cells that have never been exposed to an antigen and, therefore, never been activated. They remain at a quiescent stage with minimal cell division. To become an effector T cells, there is a special requirement. Once naive T cells are activated, it becomes effector T cells and performs a variety of effector function as described above.
I challenge here that certain CD4 T cells with effector function, therefore considered effector T helper cells, could be derived from HST, but not from naive T cells.
Several effector T cells could be directly generated from HST (CCR5+ CD4 T cells). That has been the central theme of my hypothesis. IFN-g producing CD4 Th1 cells are generated in two waves after infection. It is expected that early IFN-g producing cells have been considered as effector memory CD4 T cell populations that were generated even before pathogenic challenge. Late arising Th1 cells are expected to be the newly formed Th1 cells from the pathogenic challenge derived from naive T cells. However, these two types of Th1 cells are not only different from their timing of action, but they do not share requirement for their generation. Early IFN-g producing Th1 cells, unlike conventional Th1 cells, do not even require IL-12'IL-12R/STAT4 axis for their differentiation from naive T cells. Instead, they use IFN-g/IFN-gR/STAT1 axis. These differences suggest that they are different type of Th1 cells. I called the early IFN-g producer Th1-like CD4 T cells, instead of Th1 CD4 T cells. When infected with SIV in non-human primates, early IFN-g producing CD4 T cells (Th1-like) cells are missing, suggesting they could be derived from the HST, but not from naive T cells. We will be able to answer this question when we were able to differentiate Th1 and Th1-like cells. It is also expected that early Th1-like cells could be involved in a broad range of protective immune responses, unlike antigen specific Th1 cells. They could be involved in innate immune responses, in addition to initiating adaptive immune responses by activating antigen presenting cells through CD40L-CD40 interaction (indirect hint by CD40L+ CD4+ memory T cells migrate in a CD62P-dependent fashion into reactive lymph nodes and license dendritic cells for T cell priming. Martín-Fontecha A, Baumjohann D, Guarda G, Reboldi A, Hons M, Lanzavecchia A,Sallusto F.
J Exp Med. 2008 Oct 27;205(11):2561-74. Epub 2008 Oct 6.).
The lack of HST after being deleted by HIV will affect the generation of effector T cells that are derived from them such as, Th1-like, Th2-like, TFH, Th17 cells and gut LP Treg cells. This is different from our current paradigm.
Key words
effector CD4 T cells, HIV, AIDS, Th1, Th2, Th17, TFH, Treg cells, Th1-like, Th2-like, extrafollicular TFH, isotype switch, affinity maturation, HST, BnAb, Siliciano, Chase, Dandekar, Sekaly,
