Memory CD4 T cells and the neonatal gut

I have found a short paper on the potential mechanism of how HIV virus may be transmitted between mother and child. I think it is interesting because it not only provides the information which may be useful for a given pathology but it also poses some questions as to the basic immunology processes. The main theme of the paper is the quest for HIV targets among neonatal CD4 T cells. As it is known the virus tends to infect memory CD4 T cells but these cells are practically absent in the cord blood. Thus authors inspect neonatal CD4 T populations from various anatomical compartments and find that CD4 T cells bearing a memory marker and HIV co-receptor abound at the intestinal mucosa.

The link:

CD4 T cells collected for this study derive from children born to healthy mothers therefore this report asks only about the potential mechanism of mother to child transmission. Authors follow CD4 T cells that bear also CD45RO (which is a marker of memory state) and CD5 (HIV uses this molecule as a co-receptor to infect an individual cell – only CD5-tropic strains tend to become transmitted form mother to child). The main conclusion of this publication is that the population of CD4+CD45RO+CD5+cells (the potential HIV target according to the current state of knowledge) exists at the neonatal gut mucosa but not in the lymph nodes, spleen or blood. Additionally, around half of this intestinal memory CD4+CD45RO+CD5population appears to be differentiated into Th17 phenotype since these cells express RORγt transcription factor and CCR6.  In an in vitro experiment investigators also show that neonatal CD4 T cells from the gut are more susceptible to HIV infection than CD4 T cells from the lymph nodes or blood.

Based on obtained data authors propose a model of how HIV gets transmitted from mother to child. According to them the virus may take the oral route of transmition by the ingestion of infected body fluids during the delivery or milk shortly afterwards. I lack the clinical knowledge to critically evaluate such proposal. But I have more basic question instead. This paper not only shows the presence of memory CD4 T cells population at the neonatal gut mucosa but it also provides the evidence that these memory cells underwent substantial clonal expansion that must have happened in utero. I would like to know more details on the nature of antigenic challenge that underlies such prenatal activation of the adaptive immune system.

Bunders MJ, van der Loos CM, Klarenbeek PL, van Hamme JL, Boer K, Wilde JC, de Vries N, van Lier RA, Kootstra N, Pals ST, & Kuijpers TW (2012). Memory CD4+CCR5+ T cells are abundantly present in the gut of newborn infants to facilitate mother-to-child transmission of HIV-1. Blood, 120 (22), 4383-90 PMID: 23033270

On the wild mice and autoimmunity

Only the relatively small part of mammalian genome is formed by protein-coding sequences. The long stretches between these protein-bearing fragments contain other components which could be either non-transcribed regulatory elements or the variety of non-translated RNAs many of which are also taking part in the regulation of gene expression. This intricate network influences the decision whether a given protein is present in the particular physiological situation and how much of it is available. Therefore the issue how proteins are regulated may in fact be equally or more important than the structural differences in coding parts of the protein in question. The problem of transcriptional regulation that affects the autoimmunity development composes the leading theme of the publication I am discussing today. Like the majority of experimental studies this work uses the cornerstone model organism – the mouse Mus musculus. However, unlike the most it provides also some glimpse into the natural populations of rodents.

The link:

The particular problem analyzed by this publication comprises the association between FcγRIIb receptor and the aptitude to develop autoimmune reactions. Authors analyze the populations of wild mice from various part of the globe and find out that the vast majority of them are in the possession of FcγRIIb haplotype that is also present in several laboratory mice known for their propensity to develop the autoimmunity. Such arrangement is of interest because it suggests that in the wild populations such autoimmunity-correlated variant of FcγRIIb may actually be positively selected.

FcγRIIb is the receptor that recognizes the constant portion of an antibody that has switched to the IgG isotype and unlike other receptors that also bind to IgG its ligation on B cells causes the modulation of immune responses. To gain an insight of how FcγRIIb haplotype which is predominantly present in the wild mice may influence the immune response of the classic laboratory strain C57BL/6 (which itself has FcγRIIb haplotype not associated with the autoimmunity) investigators exchange the copies of that receptor by the knock-in approach and study the immune parameters of the resulting strain.

It turns out that the alterations between two haplotypes lie in their transcriptional regulation. In the non-autoimmune setting (as demonstrated by C57B/6 strain) FcγRIIb is upregulated on germinal center B cells whereas the knocked-in variant of this receptor cancels this up-regulation. Additionally, when compared to to C57BL/6 line the novel knock-in strain displays the reduced amount of FcγRIIb on activated B cells, splenic transitional B cells and bone marrow residing pre-B cells. Authors pin down the difference in the DNA sequence that underlies the disparate regulation of two variants and propose the transcription factor which may be responsible for the up-regulation seen when the non-autoimmune haplotype is present. Finally, investigators also show that the two haplotypes in questions differ in qualitative terms that comprise the number of germinal center B cells, affinity maturation and autoimmunity development.

Why do I think that this report is interesting? When you look at the paper conclusions from the broader perspective they seem to confirm the notion that in the natural circumstances the autoimmunity is not a problem. The widespread presence of that particular FcγRIIb haplotype among the wild mice suggests that at least for germinal center B cells the natural selection may have favored the situation where the efficiency of immune reaction is maximized even at the cost of potential collateral damage. Maybe it looks like the obvious notion but it is good to have some hard data that confirm it.

Espeli, M., Clatworthy, M., Bokers, S., Lawlor, K., Cutler, A., Kontgen, F., Lyons, P., & Smith, K. (2012). Analysis of a wild mouse promoter variant reveals a novel role for Fc RIIb in the control of the germinal center and autoimmunity Journal of Experimental Medicine, 209 (12), 2307-2319 DOI: 10.1084/jem.20121752

First prime and then pull – the novel immunization approach

Some areas of our body enjoy a special status as far as the immune reaction is concerned. Anatomical entities like the gut or female genital tract as well as other mucosal surfaces do not support the same extend of protective response compared to many non-mucosal tissues. This exclusion is crucial to avoid the unwanted inflammation in places that are regularly exposed to the outer environment but sometimes it may present a problem when there is the need to elicit the strong protective response at such privileged site. I have found an interesting report which applies the novel vaccination strategy aimed to enhance the protection against herpes simplex virus 2 which being the virus transmitted through the contact with infected body fluids often enters the body through the genital organs. The innovation that this report introduces consists of double treatment (“prime and pull”) which bypasses the restrictive entry of memory T cells into the vaginal mucosa.

The link:

The mentioned “prime and pull” strategy is the subcutaneous immunization with an attenuated strain of HSV-2 (prime) which is followed by the topical application of chemokines CXCL9 and CXCL10 to the vaginal mucosa (pull). Authors follow the localization of CD8 T cells that recognize an epitope within one of HSV-2 glycoproteins and activated CD4 T cells to show that the distal immunization event plus the localized chemokine treatment provokes the significant recruitment of activated lymphocytes to the vagina whereas the immunization alone has much weaker effect. Interestingly, this recruitment is specific to CD4 and CD8 lymphocytes and does not encompass other cell types that express the relevant chemokine receptor CXCR3.

Is the “prime and pull” approach able to provide the longstanding and reliable protection? Data demonstrate that CD8 T cells (but not CD4 T cells) are retained at vaginal mucosa after the primary response period is over. Most importantly the “prime and pull” treatment may be indeed superior in enforcing the better protective immunity to HSV-2 challenge than the immunization alone. Investigators also ask about the mechanism by which the protection is delivered by the “prime and pull” strategy. It appears that this application can prevent the virus from entering the nervous system where HSV-2 propagates past the mucosal stage of infection.

What will be the future of “prime and pull”, though? The pros are obvious – there is the simple method to enhance the mucosal migration of protective lymphocytes without the “ugly face” of immunity which in this case would be the excessive inflammation at the sensitive anatomical location. Authors speculate about the future applications ranging from HIV protection to solid tumors treatment. The method itself may also be developed as in the discussed paper it provides the optimal protection only in conjunction with the adoptive transfer of virus-specific lymphocytes. The “pull” works as well with the endogenous population of CD8 T cells; however, the protection is suboptimal in such scenario. I will follow this story.

Shin H, & Iwasaki A (2012). A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature, 491 (7424), 463-467 PMID: 23075848