Cell Differentiation Degree as a Factor Determining the Role for Different T-Helper Populations in Tuberculosis Protection

Abstract

Efficient tuberculosis (TB) control depends on early TB prediction and prevention. Solution to these tasks requires knowledge of TB protection correlates (TB CoPs), i.e., laboratory markers that are mechanistically involved in the protection and which allow to determine how well an individual is protected against TB or how efficient the candidate TB vaccine is. The search for TB CoPs has been largely focused on different T-helper populations, however, the data are controversial, and no reliable CoPs are still known. Here we discuss the role of different T-helper populations in TB protection focusing predominantly on Th17, "non-classical" Th1 (Th1^*) and "classical" Th1 (cTh1) populations. We analyze how these populations differ besides their effector activity and suggest the hypothesis that: (i) links the protective potential of Th17, Th1^*, and cTh1 to their differentiation degree and plasticity; (ii) implies different roles of these populations in response to vaccination, latent TB infection (LTBI), and active TB. One of the clinically relevant outcomes of this hypothesis is that over-stimulating T cells during vaccination and biasing T cell response toward the preferential generation of Th1 are not beneficial. The review sheds new light on the problem of TB CoPs and will help develop better strategies for TB control.

Keywords: Th1; Th17; correlates of protection; non-classical Th1; tuberculosis.

Figure 1

Model suggesting the relationships between Th17, Th1* and cTh1 populations and their potential roles in post-vaccination immunity, LTBI and active TB. (A) Current concepts of cTh1, Th17, and Th1* differentiation. cTh1 differentiate from naïve lymphocytes in the presence of IL-12 (36, 37). Th17 differentiate from naïve lymphocytes in the presence of cytokine mixture. In general, the differentiation of mouse Th17 cells depends on IL-6/TGF-β; the generation of human Th17 is driven by IL-23/IL-1β/IL-6. The involvement of TGF-β in the generation of human Th17 has been suggested by some authors, especially at low cytokine doses (36, 38, 39). When exposed to IL-12, IL-1β, or/and TNF-α, Th17 convert into IFN-γ producing Th17.1 and Th1* lymphocytes (, –43). Alternatively, Th1* may derive directly from naïve lymphocytes under the action of cytokines that have not yet been identified (40). The concept considers Th1* and cTh1 as independent lineages of CD4⁺ T-cell differentiation. (B) Suggested pathway of cTh1, Th17, and Th1* differentiation. Naive cells progressively differentiate into Th17, Th1* and cTh1/cTh1-like lymphocytes. The depth of the differentiation depends on the strength of antigenic stimulation and cytokine milieu and is different in response to vaccination, LTBI and active TB. (C) Suggested pathway of cTh1, Th17, and Th1* differentiation and the predominance of different Th populations following vaccination, during LTBI and active TB. In response to vaccination, different populations of Th cells generate. Of them, Th17 have higher survival capacity and persist longer. Following Mtb infection, Th17 are exposed to antigen, IL-12 and pro-inflammatory cytokines and differentiate into IFN-γ producing Th1* CXCR3⁺CCR6⁺ cells. The cells persist during LTBI and maintain protection against TB disease. cTh1 are generated in response to vaccination, LTBI and TB disease, but do not persist for a long time. During active TB, their magnitude increases due to their permanent generation from naïve lymphocytes and/or Th1*. The size of the circles indicates the relative prevalence and protective roles of the corresponding subsets in the indicated conditions. For each condition, prevalent pathways of T-cell differentiation are indicated in solid arrows, otherwise dashed arrows are used.