Type I IFN signaling makes T cells perforin-proof

   Upon antigen encounter, T cells become activated, proliferate and differentiate into effector or memory population. Cytokines play a fundamental role in these processes. For example, IFN receptor deficient CD8 T cells do not survive after viral infection. It is thought that type I IFN signaling in T cells imprint survival and effector differentiation quality.

   However, two new studies published in Immunity, provided an alternative and surprising explanation for the beneficial effect of type I IFN signaling in T cells. I found the results of these studies to be of sufficient significance to qualify for my review.

   One paper has two two co-first authors, Heifeng C. Xu and Melanie Grusdat (1).

   In this paper, first set of experiments showed that while in vitro wild-type (WT) and IFN-alpha receptor deficient CD8 T cells behave the same way, in vivo IFN-alpha receptor deficient CD8 T cells (unlike WT CD8 T cells) quickly disappear upon transfer into virus infected host. The same effect was seen with IFN-alpha receptor deficient CD4 T cells (smarta T cells).

   Interestingly, adoptive transfer of IFN-alpha receptor deficient CD8 T cells into virus infected host, depleted of NK cells, restored IFN-alpha receptor deficient T cells numbers. The similar effect was seen in virus infected hosts genetically deficient of NK cells (Nfil-deficient mice). These results indicated that NK cells may specifically target activated IFN-alpha receptor deficient T cells for elimination.

      In vitro experiment showed that type I IFN signaling induces MHC class I and non-classical MHC Ib (Qa-1b) molecules on the surface of T cells. These molecules were known to inhibit NK cell activity.

    Accordingly, in vitro NK cells selectively eliminated IFN-alpha receptor deficient CD8 T cells compared WT CD8 T cells via perforin-mediated pathway. Finally, adoptive transfer of IFN-alpha receptor deficient CD8 T cells into virus infected perforin-deficient hosts restored IFN-alpha receptor deficient T cells numbers and no further increase was detected after NK cell depletion.

   In sum, these results indicate that signaling through IFN-alpha receptor in T cells is necessary to prevent early elimination of T cells by primed NK cells after virus infection.

    Second paper is from Oxenius lab. The first author is Josh Crouse. It is more detailed study but with the same conclusion (2).

  This second group also observed that NK cell depletion with anti-NK1.1 or anti-Asialo GM1 antibody restored expansion of adoptively transferred IFN-alpha receptor deficient T cells (both LCMV specific P14 CD8 T cells and smarta CD4 T cells). Interestingly, only activated but not naïve T cells became sensitive to NK cells. This group also found that adoptive transfer of IFN-alpha receptor deficient P14 CD8 T cells or smarta CD4 T cells into LCMV virus infected perforin-deficient hosts restored IFN-alpha receptor deficient P14 CD8 and smarta CD4 T cells numbers and no further increase was detected after NK cell depletion. Finally, the authors found that NK cells preferentially killed IFN-alpha receptor deficient T cells in vivo and in vitro through NCR1-mediated pathway.

    In summary, these two studies showed that during acute viral infection, antigen activated T cells become sensitized to NK cell killing in absence of type I IFN signaling. Mechanistically, in absence of IFN signaling in T cells, T cells upregulate activating NCR1 ligand. Since without type I IFN signaling, inhibitory ligands like MHC class I, are not upregulated, this leads to T cell sensitization to NK cell killing via perforin.

     In my view, one important discussion missing from both studies is the role of NK cells or CD8 T cells in acute LCMV infection. Can LCMV infect type I IFN receptor deficient T cells? Why are NK cells targeting T cells at such a early stage of infection (day 3-7)? Is NK cell depletion beneficial for the virus (LCMV)-infected hosts?

David

Chronic infection and the origin of adaptive immune system

If you are interested in immunological modeling or theories (which is my special interest), this hypothetical article is for you. I think it has some unique ideas.

I would like to point out that more recent studies of jawless vertebrate immune system reveal that they also contain adaptive-like immune system, probably as diverse as of jawed vertebrates (1).

  

Med Hypotheses. 2010 Aug;75(2):241-3.

David Usharauli

Abstract

It has been speculated that the rise of the adaptive immune system in jawed vertebrates some 400 million years ago gave them a superior protection to detect and defend against pathogens that became more elusive and/or virulent to the host that had only innate immune system. 

First, this line of thought implies that adaptive immune system was a new, more sophisticated layer of host defense that operated independently of the innate immune system. 

Second, the natural consequence of this scenario would be that pathogens would have exercised so strong an evolutionary pressure that eventually no host could have afforded not to have an adaptive immune system. Neither of these arguments is supported by the facts. 

First, new experimental evidence has firmly established that operation of adaptive immune system is critically dependent on the ability of the innate immune system to detect invader-pathogens and second, the absolute majority of animal kingdom survives just fine with only an innate immune system. Thus, these data raise the dilemma: If innate immune system was sufficient to detect and protect against pathogens, why then did adaptive immune system develop in the first place? 

In contrast to the innate immune system, the adaptive immune system has one important advantage, precision. By precision I mean the ability of the defense system to detect and remove the target, for example, infected cells, without causing unwanted bystander damage of surrounding tissue. 

While the target precision per se is not important for short-term immune response, it becomes a critical factor when the immune response is long-lasting, as during chronic infection. In this paper I would like to propose new, "toxic index" hypothesis where I argue that the need to reduce the collateral damage to the tissue during chronic infection(s) was the evolutionary pressure that led to the development of the adaptive immune system.

for whole article please see

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897935/

David

Understanding self-nonself discrimination by adaptive immune system

modified from 

Usharauli, David (2010, October 30). Understanding self-nonself discrimination by adaptive immune system. 

SciTopics. http://www.scitopics.com/Understanding_self_nonself_discrimination_by_adaptive_immune_system.html

In 1969, Niels Jerne, later a Nobel laureate, predicted that "immunology will be completely solved within fifty years from now”, i.e. by 2019 (Jerne, 1969). Even earlier, in 1964, Frank Burnet, a Nobel laureate, complained that “the infant science [immunology] would soon run out of problems to solve” (Anderson, 1994). What was the basis for such a confidence? Maybe they knew better? After all, both were science demigods, acclaimed and worshipped and the modern immunology was of their creation. So what was this all about? 

The answer is the principle of self-nonself discrimination by adaptive immune system.

The adaptive immune system consists of T cells and B cells (clones). Each clone expresses a unique membrane receptor that (as the product of random gene recombination) is specific for an antigen, either self or nonself. Since an immune response can be initiated from a single clone (Stemberger et al, 2007), it is mandatory for the adaptive immune system to keep self-specific clones in check (tolerance) while at the same time allowing nonself-specific clones to respond (immunity). So how is this achieved? 

The value of any conceptual model rests on its predictive power. Initially, based on Peter Medawar’s (Nobel Lecture) experiments and Niels Jerne’s theoretical concept, the favored model was the one proposed by Frank Burnet. Burnet’s model of self-nonself discrimination required that all clones being generated during the embryonic stage when presumably only self-antigens were present (Burnet, 1957). At this stage, any clone that expressed a self-specific receptor would be deleted. Only nonself-specific clones would accumulate and subsequently respond to nonself-antigens when introduced by pathogen-invader. 

Soon, however, this model required major modification when it was shown experimentally that new clones of T and B cells are continuously generated long after birth. The problem was that according to the Burnet model, immediately after birth, each clone becomes spontaneously fully capable of responding to its cognate antigen, and given that newly generated clones can be self-specific, this scenario would have probably led to an unacceptably high frequency of self-specific responses, i.e. autoimmunity. A solution to this problem was introduced by Joshua Lederberg. According to the Lederberg model, each new clone (irrespective of whether it was generated during the embryonic stage or after birth) transits through a deletion-only stage and then it becomes spontaneously fully capable of responding to its cognate antigen (Lederberg, 1959). This deletion-only stage ensured that new clones with self-specificity would encounter their cognate self-antigens at this stage and become deleted. 

The Lederberg model, however, also failed for two reasons: first, deletion-only stage for newly generated clones was difficult to document experimentally, and second and more importantly, the Lederberg model did not account for the scenario when new self-antigens are introduced in the body, for example during puberty, pregnancy, lactation, etc. According to the Lederberg model these new self-antigens would have been considered as nonself (foreign) by the adaptive immune system and attacked, leading to unacceptably high frequency of autoimmune responses. In other words, the Lederberg model only works if self-antigens are constant (static) and it fails if self-antigens are changing (dynamic). 

All classical self-nonself discrimination models fail if self-antigens are changing. More recently, Melvin Cohn tried to save the classical self-nonself discrimination model by suggesting that the primary function for AIRE gene is to drive expression of “future” self-antigens during embryonic stage to create static view of self-antigen dynamics (Cohn, 2009).

The challenge posed by self-antigen dynamics was the major conceptual driving force behind the development of dendritic cell based innate “self-nonself” discrimination models of the past 20 years. Two models in particular completely revolutionized the modern immunology. The first one was introduced by late Charles Janeway and the second one by legendary Polly Matzinger (Janeway, 1992; Matzinger, 1994). 

In these models, “self-nonself” discrimination actually refers to immunity/tolerance fate of individual clones. Many weaknesses of Janeway’s model as it was originally understood (for example, how viruses stimulate innate immunity, how nonbacterial adjuvants, such as alum, work) is nowadays mainly resolved. While both these models can explain the immunological tolerance to changing “self”, both dendritic cell based “self-nonself” discrimination models so far failed (one in theory and another in practice) to explain the persistence of adaptive immune response to nonself (foreign) transplanted tissues. 

This maybe the result of downplaying the role that effector/memory T cells can play in perpetuating the immune response. Especially important is the relationship between effector/memory T cells and dendritic cells. If an effector/memory T cell with the self-specificity were able to deliver maturation signals to resting dendritic cells (and be equivalent in this regard to signals introduced by pathogen-invader or generated during tissue damage), then both Janeway’s and Matzinger’s models would fail because this scenario would lead to unacceptably high frequency of autoimmune responses. Interestingly, one paper published in Nature Medicine found that memory CD4 T cells were capable of inducing signals similar in nature to that induced by pathogen-invader (Strutt et al, 2010). If confirmed, this observation will necessitate yet another major modification of self-nonself discrimination model. In addition, to best of my knowledge, no one yet able to propose a working hypothesis how to incorporate Foxp3+ T regs in a predicable model of immune system function. After all, there are still 5 years left until 2019.

David Usharauli