Abstract
It is generally accepted that the flow of immunologically relevant information during the early stages of responses against pathogens is one-way, - that inflammation induced upon pattern ...recognition by highly conserved receptors of the innate immune dramatically impacts subsequent antigen-specific T and B cell responses. We asked if the reverse occurs, and if cells of the adaptive immune system can influence the character and magnitude of innate inflammatory responses. We show here that resting, antigen-specific memory CD4 T cells can dramatically alter innate inflammatory responses within 36 hours of viral infection in a manner independent of other T cells and TLR signaling. Virus-specific memory CD4 T cells transferred to naïve mice that are then challenged with influenza induce greater expression of multiple inflammatory mediators both at the site of infection and systemically upon cognate recognition of antigen in an IFN-gamma independent fashion. Our results show that the adaptive immune system can profoundly influence the character of inflammation following pathogen challenge, demonstrating a new role for memory CD4 T cells in controlling virus titers during protective immune responses.
Abstract
Here we study the expression and influence of IL-10 during murine influenza infection. We find that IL-10 has a minimal impact on the outcome of sub-lethal infection but that IL-10-deficient ...mice display dramatically increased survival compared to wild-type mice when challenged with lethal doses of virus. Administration of IL-10 receptor blocking antibodies to wild-type mice results in a similar survival advantage. Increased survival in the absence of IL-10 does not correlate with increased cellular responses, or with decreased viral titers but does correlate with improved lung function and increased expression of Th17-associated cytokines during the peak of infection.
Our studies identify highly activated, lung-resident virus-specific CD4 T cell effectors that co-produce IFNγ as the major source of IL-10 during primary influenza infection and we show that autocrine IL-10 production by responding CD4 T cells is critical in dampening influenza-specific Th17 responses.
Finally, we show that transfer of virus-specific Th17-polarized CD4 T cell effectors can protect wild-type, B cell-deficient, and T cell-deficient mice against lethal influenza challenge. We further show that Th17-polarized effectors employ novel mechanisms of protection against influenza distinct from previously established modes of protection employed by Th1-polarized CD4 T cells. Our results thus show that production of IL-10 is detrimental during high-dose primary influenza challenge, and furthermore, suggest an unexpected protective role for virus-specific Th17 CD4 T cell effectors.
Inflammation induced by recognition of pathogen-associated molecular patterns dramatically impacts subsequent adaptive responses. We asked if the adaptive immune system can also affect the character ...and magnitude of innate inflammatory responses. We find that the response of memory, but not naïve, CD4
+
T cells enhances production of multiple innate inflammatory cytokines and chemokines (IIC) in the lung, and that during influenza infection, this leads to early control of virus. Memory CD4
+
T cell induced IIC and viral control require cognate antigen recognition and are optimal when memory cells are either T helper type 1 (T
H
1)- or T
H
17-polarized, but are independent of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production and do not require activation of conserved pathogen recognition pathways. This represents a novel mechanism by which memory CD4
+
T cells induce an early innate response that enhances immune protection against pathogens.
Inflammation induced by recognition of pathogen-associated molecular patterns markedly affects subsequent adaptive responses. We asked whether the adaptive immune system can also affect the character ...and magnitude of innate inflammatory responses. We found that the response of memory, but not naive, CD4.sup.+ T cells enhances production of multiple innate inflammatory cytokines and chemokines (IICs) in the lung and that, during influenza infection, this leads to early control of virus. Memory CD4.sup.+ T cell-induced IICs and viral control require cognate antigen recognition and are optimal when memory cells are either T helper type 1 (T.sub.H1) or T.sub.H 17 polarized but are independent of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production and do not require activation of conserved pathogen recognition pathways. This represents a previously undescribed mechanism by which memory CD4.sup.+ T cells induce an early innate response that enhances immune protection against pathogens.
Inflammation induced by recognition of pathogen-associated molecular patterns markedly affects subsequent adaptive responses. We asked whether the adaptive immune system can also affect the character ...and magnitude of innate inflammatory responses. We found that the response of memory, but not naive, CD4 super(+) T cells enhances production of multiple innate inflammatory cytokines and chemokines (IICs) in the lung and that, during influenza infection, this leads to early control of virus. Memory CD4 super(+) T cell-induced IICs and viral control require cognate antigen recognition and are optimal when memory cells are either T helper type 1 (T sub(H)1) or T sub(H)17 polarized but are independent of interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a) production and do not require activation of conserved pathogen recognition pathways. This represents a previously undescribed mechanism by which memory CD4 super(+) T cells induce an early innate response that enhances immune protection against pathogens.
Abstract
Activated T cells play a central role in controlling respiratory virus infections. However, these T cells also mediate considerable pulmonary immunopathology and lung damage. The level of ...immunopathology tends to be much less in secondary compared to primary infections, but the underlying reasons for this difference are unclear. To determine if CD4 memory T cells regulate pulmonary immunopathology, we transferred influenza-specific CD4 memory T cells into naïve mice challenged with influenza virus and assessed (i) inflammation, (ii) antigen presentation, and (iii) de novo T cell stimulation in the lung environment. The presence of CD4 memory T cells during influenza infection greatly reduced the expression of pro-inflammatory cytokines and chemokines in the lungs, as well as the ability of alveolar macrophages and pulmonary dendritic cells to stimulate naïve CD4 and CD8 T cell responses directly ex vivo. CD4 memory T cells also inhibited the accumulation of newly primed CD4 and CD8 T cells in the lungs, without reducing virus titers or de novo T cell responses in the periphery. We propose that CD4 memory T cells are capable of limiting pulmonary immunopathology by preventing the influx and retention of newly primed T cells in the lungs during respiratory infections. We are currently assessing whether the effective induction of CD4 memory populations through vaccination protects against excessive pulmonary immunopathology and secondary bacterial pneumonia. Funded by NIH AI057158 NBC-Lipkin and Trudeau Institute.
Abstract only
Infection of mice with influenza (flu) viruses generates CD4 memory T cells that reduce the accumulation of newly primed CD4 and CD8 T cells in the lungs during subsequent infections, ...while allowing normal T cell priming in lymphoid organs. Since the modulation of new T cell responses by CD4 memory T cells is not due to competition for antigen, we assayed for classical regulatory T cell populations within the CD4 memory T cell pool. While there was an increase in classical Treg and Tr1 phenotype T cells after flu infection, the CD4 memory T cells did not need to express CD25, GITR, or IL‐10 to carry out their modulatory functions. Gene expression in the lungs of flu infected mice adoptively transferred with CD4 memory T cells, versus naïve CD4 T cell transfer, revealed a reduced expression of genes associated with type‐1 inflammation and increased expression of genes associated with type‐2 inflammation. Thus, we are exploring whether CD4 memory T cells prevent accumulation of newly primed T cells in the lungs due to a reduced expression of type‐1 chemoattractants or active suppression of newly primed T cell survival in a type‐2 biased lung environment. However, we have not ruled out the possibility that the modulatory CD4 memory T cells may be recruiting classical regulatory T cells to the lungs during flu infection. Determining the mechanism by which CD4 memory T cells modulate newly primed T cell responses at sites of infection, and the impact this has on the generation of subsequent memory T cell responses, will yield important insights into methods for inducing protective T cell memory to a broad range of pathogens. Funding provided by NBC‐
AI057158
‐Lipkin.
Despite many studies, the regulation of CD4
+
T cell apoptosis during the shutdown of immune responses is not fully understood. We have investigated the molecular mechanisms of IFN-
γ
in regulating ...apoptosis of CD4
+
T cells during bacillus Calmette-Guérin (BCG) infection of mice. Our data provide new insight into the regulation of CD4
+
T cell apoptosis by IFN-
γ
. As CD4
+
T cells responded to BCG infection, there was a coordinated increase in IFN-
γ
production by effector CD4
+
T cells and a coordinated IFN-
γ
-dependent up-regulation of many diverse apoptosis-pathway genes in effector CD4
+
T cells. Unexpectedly, IFN-
γ
up-regulated transcripts and protein expression of Bcl-2, Bax, Bim, Bid, Apaf-1, and caspase-9 in activated CD4
+
T cells—components of the apoptosis machinery that are involved in promoting mitochondrial damage-mediated apoptosis. Wild-type, but not IFN-
γ
knockout, CD4
+
T cells underwent apoptosis that was associated with damaged mitochondrial membranes. IFN-
γ
also up-regulated expression of cell-extrinsic signals of apoptosis, including TRAIL, DR5, and TNFR1. Cell-extrinsic apoptosis signals from TNF-
α
, TRAIL, and NO were capable of damaging the mitochondrial membranes in activated CD4
+
T cells. Moreover, activated CD4
+
T cells from BCG-infected DR5, TNFR1, and inducible NO synthase knockout mice had impaired caspase-9 activity, suggesting impaired mitochondria-pathway apoptosis. We propose that IFN-
γ
promotes apoptosis of CD4
+
T cells during BCG infection as follows: 1) by sensitizing CD4
+
T cells to apoptosis by inducing intracellular apoptosis molecules and 2) by inducing cell-extrinsic apoptosis signals that kill CD4
+
effector T cells.
Tc17, a new subset of CD8 T cells Hamada, Hiromasa; Reome, Joyce B.; Misra, Sara K. ...
The FASEB journal,
April 2008, 2008-04-00, Volume:
22, Issue:
S2
Journal Article
Peer reviewed
IL‐17 producing CD4+ (Th17) and CD8+ (Tc17) effector cells are found in the lung following both primary and secondary challenge with influenza A. Tc17 effectors can be generated in vitro by four day ...culture of naïve CD8 T cells from OT‐1 TcR transgenic mice in the presence of a cocktail of cytokines including IL‐1β, IL‐2, IL‐6, TGF‐β, IL‐21 and IL‐23 and antibodies to IFN‐γ and IL‐4. The naïve T cell numbers expand 10∼20 fold in culture and a majority of the resulting cells secrete IL‐17, TNF‐α and IL‐2 upon restimulation but very few cells that secrete IFN‐γ or are positive for granzyme B, in marked contrast to Tc1. Tc17 populations express message for IL‐17, IL‐17F and IL‐22 and smaller amounts for IL‐10 and TGF‐β̃ They do not express message for perforin and exhibit no cytolytic activity. Populations of Tc17 cells express message for RORγt and FoxP3, but are negative for T‐bet and GATA3. Populations of both Tc1 and Tc17 effectors can protect naïve recipients against lethal influenza A infection.
This work was supported by NIH AI046530.
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