TB, or not TB: that is the question -- does TLR signaling hold the answer?

Abstract

Innate immunity critically depends on signaling by Toll-like receptors (TLRs) that rely heavily on an intracellular adapter protein called myeloid differentiation factor 88 (MyD88). Adaptive immune defenses are generally thought to be orchestrated by innate immune responses and so should require intact TLR-MyD88 signaling pathways. But a surprising new study in MyD88-null mice infected with Mycobacterium tuberculosis challenges this view and instead suggests that MyD88 may not be absolutely required for a normal adaptive immune response.

Figure 1

MyD88-dependent and MyD88-independent TLR signaling pathways. Most TLRs require MyD88; however, TLR4 can transmit signals by utilizing the alternative adapters, TRAM and TRIF. Like MyD88, this sub-pathway can activate NF-κB, but can regulate transcription of target genes in a manner that may be distinct from that elicited by the classical MyD88-dependent route. HSP65, heat shock protein 65; LAM, lipoarabinomannan; LM, lipomannan; PIMs, phosphatidyl-myoinositol mannosidases; STF, soluble tuberculosis factor; TIRAP, TIR domain–containing adapter protein.

Figure 2

Bridge between innate and adaptive immunity. MTB is incorporated into phagosomes (P) of APCs by one of several receptors, which appear to have a unique impact on subsequent signaling by mechanisms that are not yet clear. TLR-dependent signaling is stimulated by association of TLRs with pathogen-associated molecular patterns located on the cell surface as well as in the phagosomes. Antigenic fragments are processed and presented by MHC class II molecules to T cells, which can then be activated provided they receive appropriate costimulatory signals transduced by engagement of T cell receptors (CD28 and CTLA-4) by CD80 (B7.1) or CD86 (B7.2) that are expressed by APCs. Normal TLR-MyD88 signaling results in rapid and potent upregulation of Th1 cytokines, which are essential for effective innate immune defense but also have a profound impact on subsequent adaptive immunity via their effects on T cell activation and maturation. Activated T cells and NK cells express IFN-γ, which stimulates activated APCs to continue to produce Th1 cytokines. However, in the absence of MyD88, expression of Th1 cytokines is markedly compromised, and Th2 cytokines may then predominate and inappropriately attenuate the defensive cytokine response.

Figure 3

Multifaceted immune responses to MTB. Professional APCs such as macrophages and DCs mount a multifaceted response to pathogen invasion that most often contains or eliminates MTB, but MyD88-dependent innate immune mechanisms appear to be critical to accomplish this task.